Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation

Resistance to chemotherapy and targeted therapy in cancer is largely due to evasion of apoptosis, but ferroptosis—an iron-dependent form of regulated cell death driven by lipid peroxidation—offers a promising alternative, particularly in aggressive and therapy-resistant subtypes. The tumor immune microenvironment plays a central role in modulating ferroptosis susceptibility: CD8⁺ T cell-derived IFNγ downregulates system Xc^- and upregulates ACSL4, while other immune cells such as Tregs, MDSCs, and macrophages further fine-tune ferroptosis through cytokine and redox signaling. Importantly, ferroptosis induction promotes immunogenic cell death, enhancing T cell infiltration and synergizing with immune checkpoint blockade to achieve sustained antitumor immunity. This review delineates the molecular basis of ferroptosis sensitivity in resistant cancers, explores immune-ferroptosis crosstalk, evaluates combination strategies with immunotherapy, and discusses challenges such as toxicity and patient stratification to advance clinical translation.

1 Introduction

1.1 Clinical background

In cancer therapy, the development of drug resistance is a major factor limiting treatment efficacy. Both chemotherapeutic agents (such as cisplatin and paclitaxel) and targeted therapeutic drugs (such as EGFR inhibitors and BRAF inhibitors) can induce resistant phenotypes in cancer cells after prolonged use (1, 2). Drug resistance often stems from apoptosis evasion, but ferroptosis offers a tumor-specific alternative, particularly in malignancies with mesenchymal features (3). —— Cancer cells evade therapy-induced death signals by upregulating anti-apoptotic proteins (such as Bcl-2 and Mcl-1) or mutating apoptosis-related genes (such as p53), ultimately leading to treatment failure (4, 5).

1.2 The unique significance of ferroptosis

Ferroptosis was formally defined in 2012 as a form of regulated cell death that depends on iron ions and is triggered by the accumulation of lipid peroxides (6). Unlike traditional forms of cell death such as apoptosis, ferroptosis exhibits a unique sensitivity in drug-resistant cancer cells. On one hand, to adapt to therapeutic stress, resistant cancer cells undergo metabolic reprogramming, resulting in iron metabolism imbalance and the accumulation of lipid peroxidation substrates (7); On the other hand, their antioxidant systems, such as the glutathione–glutathione peroxidase 4 (GPX4) axis, often exhibit functional defects, making them incapable of eliminating excessive lipid peroxides. This selective vulnerability renders ferroptosis a potential breakthrough for overcoming cancer drug resistance (8).

For instance, in drug-resistant lung adenocarcinoma, ferroptosis sensitivity is markedly enhanced due to upregulated ACSL4 expression and metabolic reprogramming, which synergize with immune crosstalk—such as CD8+ T cell-derived IFN-γ—to overcome therapy resistance (9). This tumor-specific vulnerability provides a actionable target for combination strategies.

Notably, specific cancer subtypes—such as triple-negative breast cancer, lung adenocarcinoma, clear cell renal carcinoma, and mesenchymal-type tumors with high metastatic potential—exhibit heightened susceptibility to ferroptosis due to their inherent metabolic reprogramming, iron overload, and antioxidant system deficiencies. This selective vulnerability underscores the translational promise of ferroptosis-targeting strategies, offering a novel therapeutic avenue to overcome drug resistance and improve patient outcomes in these malignancies (10).

A deeper understanding of ferroptosis in drug-resistant cancers requires addressing several key questions: what is the molecular basis underlying the sensitivity of resistant cancer cells to ferroptosis (11)? How are the ferroptosis-related metabolic networks and signaling regulatory mechanisms organized (12)? How can these mechanisms be leveraged to develop effective and low-toxicity therapeutic strategies to reverse drug resistance (13)?

2 Ferroptosis susceptibility in drug-resistant cancers: core mechanistic frameworks

The clinical management of drug-resistant cancers has long been a central challenge in oncology. Notably, these phenotypic features—such as metabolic shifts in breast cancer models—interact dynamically with the immune microenvironment, enabling ferroptosis to serve as a lever for reversing resistance via pathways like IFN-γ signaling.Recent studies have revealed that most drug-resistant cancer cells—particularly subtypes with a mesenchymal phenotype and high metastatic potential—exhibit a uniquely heightened sensitivity to ferroptosis (14, 15). This sensitivity is not random; rather, it results from the interplay between the distinct molecular phenotypes acquired under prolonged drug selection pressure and adaptive metabolic alterations. These features are primarily manifested across three key dimensions: metabolic reprogramming, defects in antioxidant systems, and remodeling of the tumor microenvironment (16). A detailed analysis of these phenotypic features not only (14)facilitates a deeper understanding of the vulnerabilities of drug-resistant cancer cells but also provides a theoretical foundation for the development of ferroptosis-targeted therapies against resistant tumors (17).

2.1 Metabolic reprogramming features

Metabolic reprogramming enables tumor cells to adapt to proliferative demands and hostile microenvironments by remodeling key metabolic pathways. In drug-resistant cancer cells, this reprogramming is further skewed toward ferroptosis sensitivity. Enhanced glutaminolysis, remodeling of lipid composition, and disruption of iron homeostasis collectively provide ample “fuel” and “catalysts” for the initiation and execution of ferroptosis. This metabolic bias is not incidental; rather, it represents a trade-off acquired during the evolution of drug resistance in cancer cells (18).

2.1.1 Enhanced glutaminolysis activity

Glutamine, as a conditionally essential amino acid for tumor cells, provides critical support for their survival and proliferation (19). Drug-resistant cancer cells enhance glutamine uptake by upregulating the glutamine transporter ASCT2 (SLC1A5).

Glutamine is subsequently converted to glutamate by glutaminase (GLS) and further deaminated to α-ketoglutarate (α-KG), which directly enters the mitochondrial matrix to participate in the tricarboxylic acid (TCA) cycle, providing energy for the cells (20). While the enhanced TCA cycle promotes ATP production via the electron transport chain (ETC), it also increases the electron leakage rates from mitochondrial complexes I and III (21, 22). These leaked electrons react with molecular oxygen to generate superoxide anions (O₂•^-), which are subsequently converted into hydrogen peroxide (H₂O₂) under the catalysis of superoxide dismutase (SOD) (23). In the presence of free iron, H₂O₂ undergoes the Fenton reaction to generate highly reactive hydroxyl radicals (•OH), providing a critical source o radicals to initiate lipid peroxidation chain reactions (24, 25). In addition, glutamine serves as a biosynthetic precursor, contributing to the synthesis of nucleotides, amino acids, and other essential biomolecules (26).

Studies have shown that in various drug-resistant cancer cells, including breast, lung, and colorectal cancers, glutaminolysis is upregulated, providing abundant reducing equivalents (NADH and FADH₂) to the mitochondrial respiratory chain and thereby promoting the generation of reactive oxygen species (ROS) (27). The accumulation of ROS not only directly damages cellular macromolecules but also activates key metabolic enzymes through oxidative modifications, further driving metabolic reprogramming (28);Simultaneously, ROS serve as critical signaling molecules, activating a variety of oxidative stress–related pathways, upregulating the expression of ferroptosis-associated genes, and enhancing the potential for lipid peroxidation, thereby increasing the sensitivity of cancer cells to ferroptosis (29). For example, in drug-resistant breast cancer cells, inhibition of glutaminolysis significantly reduces intracellular ROS levels and diminishes the cytotoxic effects of ferroptosis inducers, such as RSL3 and Erastin (30). This “glutaminolysis–mitochondrial ROS–lipid synthesis” network collectively constitutes the metabolic basis for ferroptosis sensitivity in drug-resistant cancer cells.

2.1.2 Lipidome remodeling

Dynamic remodeling of the lipidome represents another key metabolic feature underlying ferroptosis sensitivity in drug-resistant cancer cells. The functional axis composed of acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) promotes the enrichment of polyunsaturated fatty acid phospholipids (PUFA-PLs) in cellular membranes, providing abundant substrates for lipid peroxidation (31). Drug-resistant cancer cells undergo lipidome remodeling to accumulate polyunsaturated fatty acid phospholipids (PUFA-PLs)—the critical “fuel” for ferroptosis—via the ACSL4-LPCAT3 axis. ACSL4, whose expression is 2.8-fold higher in triple-negative breast cancer (TNBC) resistant tumors (vs. sensitive ones), selectively converts PUFAs (e.g., AA, AdA) to PUFA-CoA; LPCAT3 then esterifies these intermediates into membrane-bound PE-AA/PE-AdA (PUFA-PLs). The bis-allylic hydrogen atoms in PUFA-PLs (bond dissociation energy ~88 kcal/mol) are highly susceptible to •OH-induced abstraction, triggering a self-amplifying lipid peroxidation chain reaction. This remodeling is particularly prominent in mesenchymal-like resistant cells, where ACSL4 upregulation is driven by YAP/TAZ signaling (activated via reduced cell-cell contact), further linking drug resistance to ferroptosis sensitivity. This reaction exhibits strict substrate specificity: ACSL4 has a 10–15-fold higher affinity for long-chain PUFAs containing more than 20 carbon atoms compared with saturated fatty acids, while it displays minimal catalytic activity toward short-chain fatty acids (32).

The resulting PUFA-CoA esters are subsequently recognized by LPCAT3, which catalyzes their esterification at the sn-2 position of lysophospholipids, such as lysophosphatidylethanolamine (LPE), ultimately generating PUFA-PLs that are incorporated into cellular and organelle membranes (33, 34).

The high abundance of PUFA-PLs enhances ferroptosis sensitivity because the bis-allylic hydrogen atoms within the PUFA chains (located between two carbon–carbon double bonds) have very low bond dissociation energies (~88 kcal/mol) and are readily abstracted by •OH or iron-catalyzed radicals, thereby initiating lipid peroxidation chain reactions (35). For example, the arachidonic acid (AA) chain in a PE-AA molecule can be attacked by radicals to form a phospholipid radical (PL•). PL• reacts with molecular oxygen to generate a phospholipid peroxyl radical (PLOO•), which then abstracts a hydrogen atom from a neighboring PUFA-PL to form a phospholipid hydroperoxide (PLOOH) while producing a new PL•, thereby perpetuating and amplifying the chain reaction (36).

High expression of ACSL4 directly increases the PUFA-PL content in cancer cell membranes by 2–3 fold, and this elevation is significantly positively correlated with ferroptosis sensitivity.

Clinical samples and model studies further validate the clinical significance of the ACSL4–LPCAT3 axis: in drug-resistant tumor tissues from patients with triple-negative breast cancer, ACSL4 expression levels were 2.8-fold higher than in sensitive tumors, and patients with high ACSL4 expression exhibited significantly enhanced responses to ferroptosis inducers combined with chemotherapy (37);In clear cell renal carcinoma cells, LPCAT3 expression is positively correlated with the levels of PE-AA and PE-AdA. Knockout of LPCAT3 markedly reduces the proportion of membrane PUFA-PLs and significantly decreases cellular sensitivity to GPX4 inhibitors (38).

2.1.3 Iron homeostasis imbalance

Drug-resistant cancer cells, including cancer stem cells (CSCs), exhibit constitutive dysregulation of iron metabolism that prioritizes labile Fe²⁺ accumulation—an essential catalyst for ferroptosis. Unlike normal cells, which use the IRP1/IRP2-IRE system to restrict Fe²⁺ overload, resistant cells enhance Fe²⁺ availability via two non-redundant pathways (1): upregulation of transferrin receptor 1 (TfR1) (2–3-fold higher than sensitive cells) to increase iron uptake (2), activation of NCOA4-mediated ferritinophagy to degrade ferritin and release stored Fe³⁺ (subsequently reduced to Fe²⁺ by STEAP3). Recent studies confirm that this Fe²⁺ enrichment (40–60% higher LIP levels) creates a “pro-ferroptotic” state, as Fe²⁺ drives the Fenton reaction to generate hydroxyl radicals (•OH) and initiate lipid peroxidation (39). In contrast, drug-resistant cancer cells markedly elevate intracellular labile iron pool (LIP) levels by enhancing autophagy-mediated ferritin degradation (ferritinophagy) and transferrin receptor 1 (TfR1)-mediated iron uptake, providing abundant iron for the Fenton reaction and lipid peroxidation (40).

Ferritin is the primary intracellular iron storage protein, composed of 24 light and heavy chain subunits forming a hollow spherical structure capable of binding up to 4,500 Fe³⁺ ions (41). In drug-resistant cancer cells, the autophagy-related protein NCOA4 (nuclear receptor coactivator 4) is significantly upregulated. NCOA4 binds to the LC3-interacting region (LIR) of ferritin heavy chain (FTH1) and sequesters ferritin into autophagosomes. Upon fusion with lysosomes, ferritin is degraded in the acidic lysosomal environment (pH 4.5–5.0) by hydrolases such as cathepsin B, releasing Fe³⁺. This Fe³⁺ is subsequently reduced to Fe²⁺ by the lysosomal ferrireductase STEAP3 and exported into the cytosol via the divalent metal transporter DMT1 (SLC11A2). The resulting increase in the labile iron pool (LIP) markedly enhances free iron accumulation and ferroptosis sensitivity (42). The above mechanism can be seen in Figure 1.

Figure 1

Figure 1. Schematic illustration of iron metabolism dysregulation in drug-resistant cancer cells leading to ferroptosis. Transferrin-bound Fe³⁺ binds to transferrin receptor 1 (TfR1) on the cell membrane; iron regulatory proteins (IRP1/IRP2) upregulate TfR1 transcription/translation, promoting endocytosis of the transferrin-iron complex. In the acidic endosomal environment (pH 5.5–6.0), Fe³⁺ dissociates, is reduced to Fe²⁺ by STEAP3, and is exported to the cytosol via DMT1. Meanwhile, nuclear receptor coactivator 4 (NCOA4) recognizes ferritin heavy chain 1 (FTH1) of the ferritin complex (FTH1-FTL, storing ~4,500 Fe³⁺ ions), mediating ferritin sequestration into autophagosomes. Autophagosome-lysosome fusion triggers ferritin degradation by cathepsin B, releasing additional Fe³⁺ (subsequently reduced to Fe²⁺). The accumulated Fe²⁺ expands the labile iron pool (LIP), mediating the Fenton reaction to generate hydroxyl radicals (•OH). These radicals induce lipid peroxidation, leading to phospholipid hydroperoxide (PLOOH) accumulation, membrane damage, and ultimately ferroptosis in drug-resistant cancer cells.

Simultaneously, drug-resistant cancer cells enhance iron uptake by upregulating transferrin receptor 1 (TfR1, CD71). TfR1 is a key cell-surface receptor responsible for transferrin (Tf) binding and iron internalization, and its expression is regulated by IRP1/IRP2 (43). Under iron-deficient conditions, IRP1/IRP2 bind to the 3′ untranslated region (3′UTR) of TfR1 mRNA, stabilizing the transcript and promoting its translation (44). In drug-resistant cancer cells, the high metabolic activity increases iron demand, leading to persistent activation of IRP1/IRP2 and a 2–3-fold upregulation of TfR1 expression. Upon binding of transferrin-bound Fe³⁺ (Tf–Fe³⁺) in the bloodstream to TfR1, the complex is internalized via endocytosis. Following endosomal acidification, Fe³⁺ dissociates from transferrin, is reduced to Fe²⁺ by STEAP3, and subsequently released into the labile iron pool (LIP) via DMT1 (45). This multifaceted regulatory crosstalk renders iron homeostasis imbalance a “core amplifier” of ferroptosis sensitivity in drug-resistant cancer cells.

Notably, this Fe²⁺ accumulation is not accidental—it is a metabolic trade-off for drug resistance: resistant cells rely on increased iron to support rapid proliferation and DNA repair under therapeutic stress, but this dependence simultaneously amplifies their vulnerability to ferroptosis.

2.2 Defects in antioxidant systems

Drug-resistant cancer cells develop a “delicate and fragile balance” between enhanced antioxidant defenses and inherent vulnerabilities—this balance directly dictates ferroptosis susceptibility. While resistant cells upregulate the System Xc^--GSH-GPX4 axis to counteract oxidative stress (e.g., SLC7A11 overexpression in lung cancer), this defense is inherently fragile (1): System Xc^- activity is suppressed by CD8⁺ T cell-derived IFNγ (via JAK/STAT-mediated SLC7A11 downregulation), and (2) GPX4 function is dependent on GSH availability—any disruption to cystine uptake (e.g., erastin treatment) or GSH synthesis (e.g., glutaminolysis inhibition) rapidly inactivates GPX4. Importantly, CSCs and resistant subclones rely more heavily on this axis than sensitive cells, making their antioxidant defense “overloaded” and prone to collapse, thus conferring ferroptosis sensitivity (46). This defect is not a mere “loss of function” but represents an adaptive vulnerability acquired by cancer cells during the evolution of drug resistance to cope with metabolic stress.

2.2.1 Impaired function or downregulation of system Xc^-

The cystine–glutamate antiporter (System Xc^-) is a critical “gateway” for maintaining intracellular glutathione (GSH) levels, and its impaired function or downregulation represents the most common form of antioxidant system defects in drug-resistant cancer cells. System Xc^- is a 1:1 heterodimer composed of SLC3A2 and SLC7A11 subunits, localized on the plasma membrane, and functions as an antiporter exchanging one molecule of extracellular cystine (Cys₂) for one molecule of intracellular glutamate (Glu), thereby mediating cystine uptake. Once inside the cell, cystine is reduced to cysteine (Cys) by thioredoxin reductase 1 (TXNRD1) or glutathione reductase (GSR). Cysteine serves as the rate-limiting substrate for GSH synthesis, combining with glutamate and glycine under the catalysis of γ-glutamylcysteine synthetase (GCS) and glutathione synthetase (GS) to generate GSH (47, 48).

The direct consequence of transcriptional downregulation or functional inhibition of System Xc^- is insufficient GSH synthesis. As the most abundant intracellular non-protein thiol antioxidant, GSH not only serves as a crucial cofactor for GPX4 but also directly scavenges •OH and lipid radicals (49). Simultaneously, System Xc^- deficiency can trigger a vicious “oxidative stress–ER stress” cycle: GSH depletion disrupts the redox balance within the endoplasmic reticulum (ER), activating the unfolded protein response (UPR), which in turn further promotes ROS generation and exacerbates lipid peroxidation (50, 51). This cycle not only amplifies the defect in the antioxidant system but also provides a “dual driving force” for the initiation of ferroptosis. In summary, the impairment of System Xc^- function significantly enhances ferroptosis sensitivity in drug-resistant cancers, offering a promising therapeutic target for overcoming chemoresistance.Notably, certain drug-resistant cancer cells can counteract System Xc- inhibition by activating alternative cysteine acquisition pathways, such as the transsulfuration pathway mediated by cystathionine β-synthase (CBS) or direct cysteine uptake via ASCT transporters (52). Additionally, overexpression of glutamate-cysteine ligase (GCL) enhances de novo GSH synthesis, while upregulation of glutathione reductase (GR) promotes GSH regeneration from GSSG, collectively conferring resistance to ferroptosis inducers targeting the System Xc–GSH axis (53).

2.2.2 Inhibition of GPX4 activity

Glutathione peroxidase 4 (GPX4), as the only intracellular enzyme capable of directly reducing lipid hydroperoxides (PLOOH), serves as the “last line of defense” against ferroptosis. Its inhibited activity is a key factor contributing to the increased ferroptosis sensitivity of drug-resistant cancer cells (54). GPX4 belongs to the selenoprotein family, with a selenocysteine (Sec) residue at its active site. Using GSH as an electron donor, GPX4 catalyzes the reduction of PLOOH to non-toxic phospholipid alcohols (PLOH), concurrently oxidizing GSH to glutathione disulfide (GSSG) (55, 56).

In normal cells, GPX4 expression and activity are maintained at relatively stable levels to cope with basal oxidative stress. In drug-resistant cancer cells, however, GPX4 activity is inhibited primarily through three mechanisms: downregulation of protein expression, modification of the active site, and deficiency of the cofactor GSH. Expression downregulation often arises from transcriptional or translational dysregulation. For example, under hypoxic conditions, HIF-2α indirectly suppresses GPX4 transcription by regulating two key intermediate molecules. In drug-resistant clear cell renal carcinoma cells, high HIF-2α expression is negatively correlated with GPX4 levels, promoting the formation of clear cell morphology and increasing ferroptosis sensitivity (38). Active site modifications are primarily mediated by specific inhibitors. For instance, the ferroptosis inducer RSL3 covalently binds to the Sec residue at GPX4’s active site, irreversibly inhibiting its activity (57, 58);FIN56 simultaneously promotes the ubiquitin-mediated degradation of GPX4 and binds to activate squalene synthase (SQS), leading to coenzyme Q10 (CoQ10) depletion and inhibition of the mevalonate pathway, thereby doubly impairing GPX4 function (59). Cofactor GSH deficiency is a direct consequence of System Xc^- impairment. As previously described, insufficient GSH deprives GPX4 of its electron donor, preventing effective reduction of PLOOH and ultimately leading to the accumulation of lipid peroxidation products (55). These findings not only validate the central role of GPX4 in ferroptosis sensitivity of drug-resistant cancers but also provide potential biomarkers for precision therapy. Thus, targeting GPX4 inhibition represents a viable strategy to induce ferroptosis and reverse drug resistance in various cancer types, with ongoing clinical trials exploring its therapeutic potential.

Conversely, some resistant cancers develop compensatory mechanisms to evade GPX4 inhibition, including GPX4 protein overexpression through NRF2-mediated transcriptional activation or Keap1 mutations, GPX4 Sec43Ser mutation that abolishes RSL3 binding, and enhanced selenium utilization that increases GPX4 synthesis and stability (60). Furthermore, alternative antioxidant systems such as the FSP1-CoQ10 and GCH1-BH4 pathways can compensate for GPX4 loss, significantly reducing ferroptosis sensitivity and contributing to therapeutic resistance (61).

2.3 Adaptive alterations in the tumor microenvironment

The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal cells, immune cells, and the extracellular matrix (ECM). Its dynamic remodeling not only influences cancer cell proliferation and drug resistance but also modulates cellular metabolism and antioxidant systems, further amplifying ferroptosis sensitivity. Drug-resistant cancer cells adapt to TME features such as hypoxia, nutrient deprivation, and reduced cell–cell contact, forming a unique “microenvironment–cell phenotype” synergistic network. Key details of these phenotypic features and their underlying mechanisms are summarized in Table 1.

Table 1

Table 1. Ferroptosis-sensitive phenotypic features of drug-resistant cancers.

2.3.1 Hypoxic microenvironment

A hypoxic microenvironment is a common feature of solid tumors, resulting from both increased oxygen consumption due to rapid tumor cell proliferation and impaired oxygen delivery caused by abnormal tumor vasculature (76, 77). Under hypoxic conditions, cancer cells activate hypoxia-inducible factor (HIF)–related pathways to initiate a series of adaptive responses, among which lipid metabolic reprogramming represents a key regulatory mechanism.

HIF-1α is a key transcription factor in the hypoxic response and can directly or indirectly regulate the expression of multiple genes involved in lipid metabolism, including fatty acid transport proteins (FATP), fatty acid–binding proteins (FABP), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN). Upregulation of these genes enhances cancer cell uptake, synthesis, and esterification of fatty acids, thereby increasing intracellular triglyceride (TG) and phospholipid stores (78, 79). Peng and colleagues found that hypoxic trophoblast cells upregulate lnc-HZ06, which promotes SUMOylation of HIF-1α. This modification enables HIF-1α to bind the promoter region of nuclear receptor coactivator 4 (NCOA4), thereby upregulating NCOA4 transcription and protein expression. NCOA4 mediates ferritinophagy, increasing the labile iron pool and ultimately inducing ferroptosis in trophoblast cells, leading to miscarriage (80). Furthermore, HIF-1α enhances the transcription of the key glutamate transporter SLC1A1 and promotes cystine uptake, thereby contributing to ferroptosis resistance (81). This “increased lipid substrates–elevated iron catalysts” synergy renders the hypoxic microenvironment an important amplifier of ferroptosis sensitivity in drug-resistant cancer cells.

HIF-2α–mediated lipid droplet (LD) storage is a major mechanism underlying PUFA-PL accumulation under hypoxia. HIF-2α directly binds to the hypoxia response element (HRE) in the promoter region of the hypoxia-inducible lipid droplet–associated protein (HILPDA) gene, activating HILPDA transcription and promoting LD formation and maturation. As a key regulator of LDs, HILPDA inhibits adipose triglyceride lipase (ATGL) activity, reducing neutral lipid breakdown. Concurrently, it upregulates fatty acid synthase (FASN) and diacylglycerol acyltransferase (DGAT) expression, or enhances the function of lipid transport proteins such as FABP4, facilitating fatty acid accumulation in LDs and accelerating their formation (82). This storage is not a mere “lipid accumulation” but serves to reserve substrates for ferroptosis. Moreover, ROS generated under hypoxic conditions can further activate ferroptosis-related signaling pathways, synergistically enhancing cancer cell sensitivity to ferroptosis (83).

2.3.2 Reduced cell–cell contact

Cell–cell contact is critical for maintaining tissue homeostasis. Intercellular communication mediated by adhesion molecules such as E-cadherin and β-catenin regulates cell proliferation, differentiation, and death (84). During tumorigenesis and progression, the patterns of contact between cancer cells often change, which can modulate ferroptosis-related molecule expression by affecting intracellular signaling pathways.

Studies have shown that when stable adhesions are formed between cells via E-cadherin, E-cadherin can interact with the core kinases of the Hippo pathway, indirectly promoting LATS1/2 phosphorylation and activation. This, in turn, phosphorylates YAP/TAZ, retaining them in the cytoplasm and rendering them inactive. In contrast, loss of E-cadherin and reduced cell–cell contact decrease LATS1/2 activity, leading to YAP/TAZ dephosphorylation and nuclear translocation. In the nucleus, YAP/TAZ bind TEAD family transcription factors to regulate the promoter regions of ferroptosis-suppressing genes, such as SLC7A11 and GPX4, thereby promoting their transcriptional expression (85); Simultaneously, β-catenin, which is bound to the intracellular tail of E-cadherin, is released from the plasma membrane and translocates into the nucleus, where it activates downstream target genes (86).

When cell–cell contact is reduced, epithelial cells may compensatorily enhance adhesion to the ECM, activating integrins and subsequently focal adhesion kinase (FAK). FAK further phosphorylates and activates the PI3K–AKT pathway, inhibiting apoptosis. However, sustained overactivation can upregulate enzymes involved in lipid synthesis, increasing the accumulation of polyunsaturated fatty acids (PUFAs) and providing molecular targets for ferroptosis (87). Similarly, Nrf2, the master transcription factor regulating antioxidant genes, is normally sequestered in the cytoplasm by Keap1. When reduced cell–cell contact enhances oxidative stress, excessive AKT activation may phosphorylate Keap1, promoting its degradation. However, sustained stress can lead to Nrf2 nuclear translocation fatigue, ultimately suppressing GPX4 expression, directly resulting in lipid peroxide accumulation and triggering ferroptosis (84).

2.3.3 The role of other immune cells in regulating ferroptosis

Beyond CD8+ T cells, multiple immune cell populations within the tumor microenvironment (TME) critically influence ferroptosis sensitivity. Regulatory T cells (Tregs) can suppress ferroptosis by secreting anti-inflammatory cytokines such as IL-10, which inhibits lipid peroxidation and stabilizes antioxidant defenses in cancer cells, thereby promoting therapy resistance. This IL-10-mediated suppression is driven by activation of the STAT3 signaling pathway in cancer cells: IL-10 binds to its receptor (IL-10R) on cancer cell membranes, triggering STAT3 phosphorylation and nuclear translocation. Phosphorylated STAT3 then upregulates the transcription of antioxidant genes (e.g., GSTP1 and SLC7A11), reinforcing the glutathione-dependent antioxidant barrier and dampening ferroptosis. Notably, this Treg-IL-10-STAT3 axis not only protects cancer cells from ferroptosis but also sustains an immunosuppressive tumor microenvironment (TME)—a key immunomodulatory consequence that limits the efficacy of ferroptosis-based monotherapies. Myeloid-derived suppressor cells (MDSCs) contribute to ferroptosis resistance by producing arginase-1, which depletes arginine and reduces nitric oxide production, altering redox homeostasis and protecting tumors from iron-dependent death (88). Arginase-1-mediated arginine depletion not only impairs nitric oxide (NO)-dependent ferroptosis (via reduced NO-induced lipid peroxidation) but also suppresses the activation of CD8⁺ T cells—an essential component of antitumor immunity. This dual effect of MDSCs (ferroptosis resistance + T cell suppression) creates a feedforward loop that exacerbates immunological tolerance: reduced ferroptosis in cancer cells limits the release of immunogenic damage-associated molecular patterns (DAMPs), while arginine depletion directly blunts T cell-mediated cytotoxicity. Targeting this arginase-1-NO-ferroptosis axis thus represents a promising strategy to co-modulate immunometabolism and restore antitumor immunity. Natural killer (NK) cells can induce ferroptosis in target cells through the release of perforin and granzymes, which trigger mitochondrial dysfunction and enhance reactive oxygen species (ROS) generation, offering a complementary cytotoxic mechanism to T cell-mediated immunity (89). Mechanistically, perforin forms pores in cancer cell membranes to facilitate granzyme B entry, which then cleaves mitochondrial antiviral-signaling protein (MAVS)—a key adaptor of innate immune signaling. MAVS cleavage disrupts mitochondrial electron transport chain (ETC) integrity, increasing electron leakage and superoxide anion (O₂•^-) production. In the presence of labile iron (expanded in drug-resistant cancer cells), O₂•^- is converted to hydroxyl radicals (•OH) via the Fenton reaction, accelerating lipid peroxidation. This NK cell-perforin-granzyme B-MAVS axis links innate immune cytotoxicity to ferroptosis, highlighting a novel immunomodulatory route to bypass apoptosis resistance in cancer. Macrophages, particularly the M2 phenotype, modulate ferroptosis by secreting transforming growth factor-beta (TGF-β), which promotes antioxidant responses and iron sequestration, TGF-β exerts its effects via activation of the Smad2/3 signaling pathway: upon binding to TGF-β receptors (TβRI/II) on cancer cells, Smad2/3 is phosphorylated and forms a complex with Smad4, which translocates to the nucleus to upregulate ferroportin (FPN1)—the primary iron export protein. Increased FPN1-mediated iron efflux reduces the labile iron pool (LIP), limiting Fenton reaction-driven lipid peroxidation. Concurrently, TGF-β/Smad signaling upregulates GPX4 expression, further reinforcing ferroptosis resistance. This M2-TGF-β-Smad-FPN1 axis underscores how immunosuppressive macrophages shape the TME to protect cancer cells from ferroptosis, emphasizing the need to target M2 polarization alongside ferroptosis induction for effective immunomodulation, thereby desensitizing cancer cells to ferroptosis inducers. This multifaceted regulation underscores the complexity of immune-ferroptosis crosstalk and highlights potential targets for combination therapies (90).

Collectively, these immune cell-ferroptosis interactions are not isolated regulatory events but integral to immunomodulation in drug-resistant cancers: CD8⁺ T cells and NK cells leverage ferroptosis to enhance antitumor immunity, while Tregs, MDSCs, and M2 macrophages exploit ferroptosis resistance to suppress immune responses. Dissecting these cross-talk mechanisms—such as IFNγ-JAK/STAT, IL-10-STAT3, and TGF-β-Smad pathways—provides a molecular basis to design combinatorial strategies (e.g., ferroptosis inducers + immune checkpoint inhibitors) that align ferroptosis activation with immunomodulation, ultimately overcoming therapy resistance.

Furthermore, the interplay between CD8+ T cells and other immune components, such as Tregs and macrophages, creates a dynamic network that can either amplify or suppress ferroptosis, providing new avenues for therapeutic intervention.

3 Core mechanisms driving ferroptosis in drug-resistant cancers

Unlike apoptosis, necrosis, and autophagy, ferroptosis exhibits distinct morphological, biochemical, and genetic characteristics (91). At the molecular level, multiple core regulatory systems exist: the classical glutathione peroxidase 4 (GPX4)–mediated system suppresses ferroptosis by clearing lipid peroxides, whereas the ferroptosis suppressor protein 1 (FSP1)–mediated system operates through the generation of radical-trapping antioxidants (92). Furthermore, the SMURF2–GSTP1 axis and the “sex hormone–MBOAT1/2–phospholipid remodeling” axis also contribute to ferroptosis regulation through distinct mechanisms, collectively forming the molecular regulatory network of ferroptosis in drug-resistant cancer cells (92, 93).

While separately detail iron metabolism and antioxidant defenses for organizational clarity, these systems are intrinsically interconnected in regulating ferroptosis sensitivity (94). Iron-driven lipid peroxidation and antioxidant responses function as complementary partners in a finely tuned regulatory network: iron metabolism provides the catalytic components (Fe2+) and lipid substrates (PUFA-PLs) necessary for peroxidation initiation, while antioxidant systems determine the threshold at which this peroxidation becomes lethal (95). Specifically, the labile iron pool (LIP) generated through ferritinophagy and TfR1-mediated uptake directly fuels the Fenton reaction, producing hydroxyl radicals that initiate lipid peroxidation; concurrently, the System Xc–GSH-GPX4 axis and FSP1-CoQ10 system work to contain this peroxidation within survivable limits (96). In drug-resistant cancers, the simultaneous upregulation of iron acquisition pathways and impairment of antioxidant defenses creates a perfect storm that dramatically lowers the threshold for ferroptosis induction, making these cells uniquely vulnerable to ferroptosis-based therapies.”

3.1 System Xc^-–GSH–GPX4 axis: the classical ferroptosis defense system

Classical ferroptosis inducers target the System Xc^-–GSH–GPX4 axis, which plays a central role in regulating the antioxidant system and lipid peroxidation (93), This pathway consists of three key molecules acting in series, collectively forming a robust antioxidant barrier (97). Inhibition of the System Xc^-/GSH/GPX4 axis can effectively promote ferroptosis in cancer cells (46).

3.1.1 System Xc^-: The key “gateway” for cystine uptake

System Xc^- is a chloride-dependent, sodium-independent antiporter localized on the plasma membrane, composed of a light chain subunit SLC7A11 (xCT) and a heavy chain subunit SLC3A2 (CD98) in a 1:1 stoichiometric ratio (98). Among them, SLC7A11 serves as the functional transport subunit, specifically binding and importing extracellular cystine (Cys₂) while exporting intracellular glutamate (Glu), achieving a 1:1 substrate exchange (99). As a key precursor for GSH synthesis, the efficiency of cystine uptake directly determines cellular antioxidant capacity and resistance to ferroptosis (100, 101).

In drug-resistant cancers, SLC7A11 expression is closely linked to ferroptosis sensitivity. For instance, in resistant models of lung and breast cancer, SLC7A11 is frequently overexpressed, enhancing cystine uptake to promote GSH synthesis and thereby increasing cancer cell resistance to ferroptosis (102, 103). Conversely, inhibition of SLC7A11 transport function can significantly impair System Xc^- activity and promote ferroptosis (104). Currently, three mechanisms regulating SLC7A11 function have been identified. The first involves small-molecule inhibitors, such as erastin and sulfasalazine, which directly suppress transport activity by binding to specific sites on SLC7A11 (105, 106); The second mechanism involves competitive inhibitors that occupy the substrate-binding site of SLC7A11, thereby interfering with cystine uptake (106); The third mechanism operates at the genetic level: transcription factors such as ATF3 and p53 can directly repress SLC7A11 transcription, while microRNAs, such as miR-26b, inhibit SLC7A11 translation by targeting its mRNA, ultimately downregulating System Xc^- function (107, 108).

3.1.2 Glutathione: The major intracellular water-soluble antioxidant

GSH is the primary water-soluble antioxidant within cells and an essential cofactor for glutathione peroxidase 4 (GPX4) function. Cystine imported via SLC7A11 is reduced intracellularly to cysteine, which subsequently participates in GSH synthesis (46). GSH plays a crucial role in maintaining intracellular homeostasis, particularly in response to oxidative stress and toxic insults (46). One of its primary functions is to catalyze the reduction of lipid peroxides to non-toxic alcohols via glutathione peroxidases (GPXs), thereby protecting cells from oxidative damage (109). Furthermore, the balance between the reduced (GSH) and oxidized (GSSG) forms of glutathione is regulated by various intracellular enzymes, such as glutathione reductase, whose activity directly affects GSH availability (109). Thus, intracellular GSH levels directly determine the capacity to scavenge lipid peroxides and serve as a critical “metabolic barrier” enabling drug-resistant cancer cells to resist ferroptosis.

3.1.3 Glutathione peroxidase 4 (GPX4)

In drug-resistant cancer cells, GPX4 expression and activity are generally elevated. Its expression is not only influenced by upstream GSH levels but also regulated by signaling pathways such as mTORC1 (46, 110). For example, mTORC1 can induce GPX4 protein synthesis via the Rag-mTORC1-4EBP axis (111). Additionally, KLF11 can suppress GPX4 transcription by binding to its promoter region, thereby reducing cellular resistance to ferroptosis (112). PX4 activity is also indirectly regulated by GSH availability: when System Xc^- function is impaired, leading to insufficient GSH synthesis, GPX4 lacks the necessary electron donor to effectively eliminate PLOOH, resulting in the accumulation of lipid peroxides.

Upregulation of the System Xc^-–GSH–GPX4 axis represents a central strategy by which drug-resistant cancer cells resist ferroptosis. Inhibition of any component of this pathway—such as blocking SLC7A11 with erastin or directly inhibiting GPX4 with RSL3—can effectively induce ferroptosis in resistant cancer cells (110, 113).

In the GPX4 catalytic cycle, GPX4–SeH is oxidized by PLOOH to GPX4–SeOH, and GSH reduces SeOH to further activate GPX4, releasing GSSG and preventing GPX4 inactivation. GSSG is reduced to GSH by the cofactor NADPH. As PLOOH is reduced to PLOH by GPX4–SeH, ferroptosis is inhibited.

3.2 FSP1–CoQ10–NAD(P)H pathway: the second line of cellular defense against ferroptosis

The FSP1–CoQ10–NAD(P)H pathway is the second major ferroptosis-inhibiting system independent of GPX4. It operates in parallel with the classic System Xc^-–GSH–GPX4 axis, together forming a “dual barrier” against lipid peroxidation in cells (114). This pathway consists of three core components: ferroptosis suppressor protein 1 (FSP1, formerly AIFM2), coenzyme Q10 (CoQ10), and NAD(P)H (115). Its uniqueness lies in being GSH-independent, providing an alternative ferroptosis defense mechanism for drug-resistant cancer cells (116).

3.2.1 FSP1 regulation of ferroptosis

FSP1 is a flavin-containing oxidoreductase. The N-terminal myristoylation site in its structure allows FSP1 to localize to subcellular structures such as the plasma membrane and Golgi apparatus, exerting antioxidant effects in close proximity (117). Functionally, FSP1 uses NAD(P)H as an electron donor to reduce ubiquinone (CoQ10) to ubiquinol (CoQ10H₂) (118). Ubiquinol, as a lipid-soluble radical-trapping antioxidant, can directly bind lipid peroxyl radicals (PLOO◼), blocking the lipid peroxidation chain reaction (116).

Recent studies show that FSP1 regulation also involves non-classical substrates and metabolic pathways. For example, FSP1 can efficiently reduce vitamin K (phylloquinone, menaquinone) to its hydroquinone form (VKH₂), which also possesses potent radical-trapping capacity, inhibiting (phospho)lipid peroxidation (119). Additionally, FSP1 expression is negatively correlated with lipid synthesis enzymes ACSL4 and LPCAT3; by indirectly downregulating their activity, FSP1 reduces the accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) in the cell membrane, lowering ferroptosis sensitivity (120). SP1 also functionally interacts with the dihydroorotate dehydrogenase (DHODH) pathway, another mitochondrial CoQ reductase, which can partially resist ferroptosis (120).

3.2.2 FSP1 regulatory mechanisms: from metabolism to post-translational modifications

FSP1 function is regulated at multiple levels including cellular metabolism, transcriptional control, and post-translational modifications. Metabolically, as an NAD(P)H-dependent oxidoreductase, FSP1 activity is closely linked to cellular energy metabolism. Cancer cells with high glycolytic activity (e.g., tumors with pronounced Warburg effect) have elevated NADH levels, providing sufficient electron donors for FSP1 and enhancing its anti-ferroptotic capacity. Conversely, inhibition of glycolysis or mitochondrial oxidative phosphorylation can limit NAD(P)H supply, weakening FSP1 function (121).

At the transcriptional level, NRF2 and BACH1 are key regulators. NRF2, as the central transcription factor for antioxidant responses, can directly bind antioxidant response elements (AREs) in the FSP1 promoter to upregulate its expression. BACH1 competitively binds ARE sites, inhibiting NRF2, downregulating FSP1 expression, thereby promoting ferroptosis (122).

Post-translational modifications of FSP1 are also critical. TRIM21, an E3 ubiquitin ligase, mediates K63-linked ubiquitination at FSP1 residues K322 and K366, promoting FSP1 membrane translocation and enhancing anti-ferroptotic activity (117). FSP1 stability is further regulated by m6A RNA methylation: YTHDC1 recognizes m6A sites in the 3’UTR of FSP1 mRNA, recruiting CSTF3 to mediate selective polyadenylation, generating unstable short 3’UTR FSP1 mRNA. When YTHDC1 is downregulated, HuR-stabilized long 3’UTR FSP1 mRNA is formed, resulting in increased FSP1 protein levels (123).

3.2.3 Parallel operation of the FSP1–CoQ10–NAD(P)H pathway with other systems

Although the FSP1–CoQ10 system can independently exert anti-ferroptotic effects apart from GPX4, under physiological conditions, these two systems usually work synergistically, providing multi-layered antioxidant defense (124). Spatially, FSP1 primarily localizes to the plasma membrane, generating CoQ10H₂ to protect membrane lipids from oxidative damage, while GPX4 is broadly distributed in mitochondria, ER, and other organelle membranes, clearing PLOOH in subcellular compartments (116). This division allows precise protection against lipid peroxidation in different regions, explaining why FSP1 expression levels are negatively correlated with ferroptosis sensitivity; cancer cells with high FSP1 expression often exhibit stronger resistance to GPX4 inhibitors (125).

Beyond GPX4, FSP1 intersects with multiple antioxidant systems. ALDH7A1 can generate membrane-bound NADH to supply electrons for FSP1 while consuming reactive aldehydes to reduce lipid peroxidation (121). Interestingly, ferroptosis stress activates AMP-activated protein kinase (AMPK), promoting ALDH7A1 membrane localization and further stabilizing FSP1 membrane association, forming a positive feedback loop (121). Another cooperative mechanism involves heme oxygenase-1 (HO-1): HO-1 degradation increases ferroptosis sensitivity, whereas HO-1 overexpression reduces ROS and lipid peroxidation accumulation, inhibiting ferroptosis (126). HO-1 may indirectly affect FSP1 function by regulating intracellular iron levels, as it is the key enzyme for heme degradation (126). Additionally, ferritin heavy chain 1 (FTH1) has functional connections with FSP1; miR-375-3p can simultaneously downregulate FTH1 and FSP1 expression, jointly promoting ferroptosis (127). The FSP1-mediated pathway provides an alternative mechanism to suppress ferroptosis, particularly in cancers with GPX4 resistance, highlighting its clinical relevance as a complementary target for combination therapies.

3.3 The SMURF2–GSTP1 axis: a third major ferroptosis regulatory system

The SMURF2–GSTP1 axis is a newly identified ferroptosis regulatory pathway, whose core mechanism involves the dynamic balance between ubiquitin–proteasome–mediated protein degradation and antioxidant activity, providing a novel perspective for understanding GPX4-independent ferroptosis regulation (93). Under basal conditions, glutathione S-transferase P1 (GSTP1) maintains cellular redox homeostasis through selenium-independent antioxidant activity. Upon ferroptosis-inducing signals, SMAD-specific E3 ubiquitin ligase 2 (SMURF2) mediates the ubiquitination and degradation of GSTP1, weakening the antioxidant defense and ultimately triggering ferroptosis (128).

3.3.1 GSTP1: an important endogenous inhibitor of ferroptosis

GSTP1, a core member of the GST superfamily, exerts dual antioxidant functions (129, 130). First, GSTP1 possesses selenium-independent glutathione peroxidase activity, directly neutralizing lipid peroxides (93). Second, GSTP1 catalyzes the conjugation of toxic lipid peroxidation products such as 4-hydroxynonenal (4-HNE) with GSH, facilitating detoxification and excretion of these harmful compounds (128).

In pancreatic cancer, GSTP1 has been shown to protect cells from radiation-induced ferroptosis (131). Radiation upregulates ACSL4 expression to induce ferroptosis, while GSTP1 overexpression reduces ACSL4 levels and increases GSH content, thereby enhancing cancer cell resistance to irradiation (131). Similarly, in doxorubicin-treated breast cancer cells, GSTP1 promotes autophagy to counteract drug-induced ferroptosis (132). These findings indicate that GSTP1 serves as a key mediator of therapy resistance across multiple cancer types.

Notably, GSTP1 expression is regulated by multiple factors. The small antigen (s-HDAg) of hepatitis delta virus (HDV) specifically binds GSTP1 mRNA and suppresses its expression, leading to ROS accumulation and cell death (133). At the transcriptional level, NRF2 acts as the primary positive regulator of GSTP1 expression (134), whereas AP-1 may suppress its transcription (135). Clinically, these factors play important roles in inhibiting the antioxidant function of the SMURF2–GSTP1 axis and promoting ferroptosis in cancer cells.

3.3.2 Molecular characteristics of SMURF2 and its role in protein homeostasis

SMURF2, a key member of the HECT-type E3 ubiquitin ligase family, exerts its central role in ferroptosis regulation by recognizing and degrading GSTP1 (136, 137). Upon ferroptosis-inducing stimuli (e.g., oxidative stress or GPX4 inhibition), SMURF2 becomes activated and binds GSTP1 via its HECT domain, mediating K48-linked ubiquitination. The ubiquitinated GSTP1 is then recognized and degraded by the proteasome, resulting in a sharp decline in antioxidant capacity and accumulation of lipid peroxides (93). This mechanism establishes the SMURF2–GSTP1 axis as the third major ferroptosis regulatory system, alongside GPX4 and FSP1.

Beyond GSTP1 regulation, SMURF2 can also ubiquitinate and degrade Dishevelled (DVL) proteins, thereby modulating the Wnt signaling pathway (136). This pathway is closely associated with cellular metabolism and oxidative stress, and its aberrant activation may enhance ferroptosis resistance by upregulating SLC7A11 expression. In addition, SMURF2 participates in regulating HIF-1α stability, influencing tumor hypoxia adaptation and metabolic reprogramming, thereby indirectly affecting ferroptosis sensitivity (137).

3.3.3 Cooperation and competition between SMURF2 and other ubiquitination systems in ferroptosis regulation

The ubiquitin–proteasome system (UPS) consists of various E1, E2, and E3 enzymes, and different E3 ligases can act cooperatively or antagonistically in ferroptosis regulation by targeting the same or different substrates.

NEDD4L (NEDD4-like E3 ubiquitin ligase) suppresses ferroptosis by ubiquitinating and degrading lactotransferrin (LTF), thereby reducing intracellular iron accumulation (138). LTF, a key iron-transporting protein that binds and transfers Fe³⁺, upon degradation, limits extracellular iron uptake, lowers the substrate concentration for the Fenton reaction, and consequently decreases ROS generation and lipid peroxidation (138); In contrast, SMURF2 promotes lipid peroxide accumulation by degrading the antioxidant protein GSTP1. The two ligases thus target distinct ferroptosis control points — iron metabolism (NEDD4L) and antioxidant defense (SMURF2) — and may cooperatively amplify ferroptotic signaling under specific stress conditions (138, 139). This cooperation appears tumor-type specific: in iron overload–induced ferroptosis, NEDD4L-mediated inhibition of iron uptake predominates; whereas under oxidative stress–induced ferroptosis, the SMURF2–GSTP1 axis plays a more crucial role. Moreover, SMURF2 and NEDD4L expression may be co-regulated by upstream stress signaling, allowing simultaneous activation to intensify ferroptotic responses.

3.3.4 Hippo-YAP pathway regulation of ACSL4 transcription

Beyond the canonical GPX4, FSP1, and GSTP1 pathways, emerging evidence implicates the Hippo-YAP signaling axis as a key regulator of ferroptosis resistance through transcriptional control of ACSL4. Yes-associated protein (YAP), the primary effector of the Hippo pathway, directly binds to TEAD transcription factors and activates ACSL4 promoter activity, enhancing ACSL4 mRNA and protein expression (93).This upregulation increases polyunsaturated fatty acid phospholipid (PUFA-PL) synthesis, thereby amplifying lipid peroxidation and ferroptosis sensitivity. Conversely, Hippo pathway activation via LATS1/2 phosphorylates and inactivates YAP, leading to nuclear exclusion and reduced ACSL4 transcription, which confers ferroptosis resistance (140). This mechanosensitive pathway integrates cellular stress signals with lipid metabolic reprogramming, providing a novel therapeutic target for modulating ferroptosis in drug-resistant cancers.

3.4 “Sex hormone–MBOAT1/2–phospholipid remodeling” axis: a novel pathway regulated by sex hormones

The “sex hormone–MBOAT1/2–phospholipid remodeling” axis represents a ferroptosis regulatory pathway independent of the above three antioxidant mechanisms. The surveillance mediated by GPX4, FSP1, and GSTP1 acts by reducing PL hydroperoxides and terminating PL oxidation chains at specific stages of PL peroxidation (46, 92). Unlike the above mechanisms, MBOAT1/2 reduce the amount of PL–PUFA (polyunsaturated fatty acids) by increasing PL–MUFA (monounsaturated fatty acids), thereby decreasing PL–PUFA levels upstream (92).

3.4.1 Biological functions of MBOAT1 and MBOAT2

MBOAT1/2 are membrane-bound O-acyltransferases that inhibit ferroptosis by remodeling the composition of cellular membrane phospholipids. Specifically, MBOAT2 selectively transfers monounsaturated fatty acids (MUFA) to lysophosphatidylethanolamine (lyso-PE), thereby increasing cellular PE–MUFA and correspondingly reducing PE–PUFA (polyunsaturated fatty acids) (92, 141).

MBOAT1, also known as LPEAT1, transfers oleic acid (OA) to lysophosphatidylethanolamine (lyso-PE) and lysophosphatidylserine (lyso-PS). Similar to MBOAT2, MBOAT1 suppresses ferroptosis through PL remodeling and preferentially promotes PE–MUFA formation (92). In addition, MBOAT1 significantly reduces RSL3-induced lipid peroxidation, which may result from the reduction of PE–AA (phosphatidylethanolamine bearing an arachidonoyl moiety) (92).

3.4.2 Regulatory mechanisms of sex hormones on MBOAT1/2

The expression of MBOAT2 is regulated by the androgen receptor (AR) and may serve as a potential therapeutic target in cancers such as prostate cancer (92, 141, 142). Androgens regulate MBOAT2 expression through the AR signaling pathway. As a ligand-activated transcription factor, AR directly binds to androgen response elements (AREs) in the MBOAT2 gene to enhance its transcription, and the use of the androgen antagonist Enzalutamide can inhibit this effect (92, 143).

Estrogens upregulate MBOAT1 expression and activity through multiple mechanisms. In the genomic pathway, estrogen receptors (ER) α and β act as transcription factors that directly bind to estrogen response elements (EREs) in the promoter region of the MBOAT1 gene to enhance its transcription (92, 144). In the non-genomic pathway, activation of the membrane-bound G protein–coupled estrogen receptor (GPER) promotes MBOAT1 expression via the ERK/MAPK signaling cascade (145, 146). Furthermore, estrogens can indirectly influence MBOAT1 activity by altering the cellular redox state, as the enzyme is sensitive to oxidative stress (92). Experimental evidence shows that MBOAT1 expression is significantly elevated in ER-positive breast cancer cells, inhibiting ferroptosis and promoting tumor growth; treatment with estrogen antagonists such as Fulvestrant can block this effect and restore cellular sensitivity to ferroptosis (92).

Beyond the four core regulatory axes detailed above, the translation of ferroptosis induction into clinical strategies for drug-resistant cancers requires explicit linking of pathways to targeted agents, applicable tumor types, and their practical advantages and limitations—an integration that is systematically summarized below.

3.4.3 systematically integrates three key pathways with direct relevance to drug-resistant cancer cell lines

First, the System Xc^--GSH-GPX4 axis remains the most well-characterized target for overcoming drug resistance. Inhibitors of this axis act through two primary strategies: blocking cystine uptake via System Xc^- or directly inactivating GPX4. Erastin and sulfasalazine are classic System Xc^- inhibitors, effective in reversing cisplatin resistance in non-small cell lung cancer (NSCLC) and paclitaxel resistance in triple-negative breast cancer (TNBC) cell lines (147). These agents exhibit high specificity for cancer cells with downregulated System Xc^- (a common phenotype in resistant subtypes), minimizing off-target effects on normal cells. However, their clinical application is limited by poor water solubility and short half-lives, requiring frequent dosing to maintain therapeutic concentrations. Direct GPX4 inhibitors, such as RSL3 and ML210, show potent activity in drug-resistant hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) cells—particularly those with acquired resistance to tyrosine kinase inhibitors (TKIs). A key advantage of GPX4 inhibitors is their ability to bypass adaptive upregulation of System Xc^-, a major resistance mechanism to erastin-like agents. Nevertheless, they often induce dose-dependent renal and hepatic toxicity due to GPX4 expression in normal tissues (148).

Second, the iron homeostasis regulatory pathway offers a tumor-selective route to induce ferroptosis in resistant cells. Agents targeting this pathway include deferoxamine (DFO, an iron chelator that disrupts iron storage) and dihydroartemisinin (DAT, which triggers lysosomal ferritin degradation). DAT has shown promise in reversing carboplatin resistance in ovarian cancer cell lines by expanding the labile iron pool (LIP) and enhancing Fenton reaction-mediated lipid peroxidation (149). Its advantage lies in synergistic effects with conventional chemotherapies, as iron overload amplifies chemotherapy-induced oxidative stress. However, DAT requires careful monitoring of systemic iron levels to avoid anemia, and its efficacy is reduced in cancer cells with upregulated ferroportin (an iron export protein). Another agent, lactotransferrin (LTF) inhibitors (e.g., NEDD4L agonists), reduce iron import in doxorubicin-resistant colorectal cancer (CRC) cells, but their use is restricted by variable LTF expression across tumor types.

Third, the ACSL4-LPCAT3 lipid remodeling pathway is critical for sensitizing mesenchymal-like drug-resistant cancer cells. Sorafenib, a multi-kinase inhibitor that indirectly upregulates ACSL4, effectively reverses TKI resistance in renal cell carcinoma (RCC) and HCC cell lines by increasing polyunsaturated fatty acid phospholipid (PUFA-PL) accumulation (150). A unique advantage of sorafenib is its dual role in inhibiting oncogenic signaling (e.g., VEGFR) and promoting ferroptosis, addressing both tumor growth and drug resistance. However, sorafenib often induces adaptive activation of the Nrf2 antioxidant pathway, which upregulates GPX4 and counteracts ferroptosis. Additionally, its efficacy is limited in cancer cells with low ACSL4 expression, such as luminal subtype breast cancer (151). Summary of Currently Used Ferroptosis-Inducing Agents Across Cancer Types can be seen in Table 2.

Table 2

Table 2. Summary of currently used ferroptosis-inducing agents across cancer types.

4 Therapeutic strategies targeting ferroptosis in drug-resistant cancer

Based on the mechanisms of ferroptosis, current research has revealed that ferroptosis is closely associated with various diseases at both organ and tissue levels, such as cardiomyopathy and intervertebral disc degeneration (164, 165). Researchers have identified multiple targeted pathways to inhibit or promote ferroptosis, offering new hope for treating various diseases (166, 167). In particular, in the treatment of drug-resistant cancers, ferroptosis-targeting strategies have shown great potential, including monotherapy, combination therapy, and optimization of delivery systems, aiming for more precise and sensitive cancer treatment (168).

4.1 Monotherapy strategies

4.1.1 Inhibition of cellular antioxidant systems

Trace element selenium, as a core molecule in ferroptosis regulation, plays an irreplaceable role in maintaining cellular redox homeostasis (169). Selenium participates in the synthesis of glutathione peroxidase 4 (GPX4), a key negative regulator of lipid peroxidation, which efficiently removes intracellular lipid peroxides and thereby maintains membrane stability (54). Cystine, the dimeric form of cysteine, is specifically transported into cells through system Xc^- (the cystine/glutamate antiporter), subsequently enhancing GPX4 catalytic activity to effectively inhibit ferroptosis (170). Multiple studies have confirmed that when system Xc^- function is inhibited, intracellular lipid peroxidation levels increase exponentially, triggering ferroptosis (101).

For example, researchers such as L. Zhou et al. found that targeting inhibition of ZDHHC8 protein activity significantly reduces GPX4 palmitoylation levels in cancer cells, blocking intracellular antioxidant defenses and markedly enhancing tumor cell sensitivity to ferroptosis (171). Erastin and RSL3, as classical ferroptosis activators, act through different mechanisms: the former inhibits system Xc^-, blocking cystine uptake and indirectly suppressing GPX4 by reducing glutathione synthesis (172);the latter directly and covalently inhibits GPX4, leading to lipid peroxide accumulation (173). However, both agents suffer from poor water solubility, low stability, and high off-target toxicity, severely limiting clinical application. Therefore, developing highly efficient targeted systems is of great significance, although clinical translation remains challenging (174).

4.1.2 Regulation of intracellular iron metabolism

As an iron-dependent form of regulated cell death, ferroptosis is closely linked to intracellular iron homeostasis—regulating iron metabolism pathways and molecules can directly influence cellular ferroptosis sensitivity (6). Due to their rapid proliferation, cancer cells exhibit significantly higher iron uptake and utilization capacity than normal cells, making them more susceptible to ferroptosis-inducing signals and providing a theoretical basis for targeting iron metabolism in cancer therapy (175).

The level of iron uptake, transferrin receptor 1 (TfR1)-mediated iron import is the primary pathway, whereas iron export is mainly controlled by ferroportin. Enhancing iron import protein function or inhibiting iron export activity increases intracellular labile iron levels, thereby heightening ferroptosis sensitivity in cancer cells (176). In addition, transient receptor potential mucolipin 1 (TRPML1), a non-selective cation channel localized on lysosomal membranes, participates in maintaining iron balance through regulation of lysosomal exocytosis (177). In cancers with hyperactivated protein kinase B (AKT), AKT phosphorylates TRPML1 at Ser343, inhibiting its ubiquitination and degradation, thereby stabilizing TRPML1’s interaction with ADP-ribosylation factor–like GTPase 8B (ARL8B). This triggers lysosomal exocytosis and promotes iron efflux, ultimately conferring resistance to ferroptosis (178). This mechanism positions TRPML1 as a potential anticancer target: TRPML1-competitive peptides can block its interaction with ARL8B, inhibit lysosomal exocytosis, increase intracellular iron accumulation, directly promote ferroptosis, and enhance tumor cell sensitivity to ferroptosis inducers, radiotherapy, and immunotherapy, thereby offering a new strategy for cancer therapy targeting ferroptosis (179).

Beyond protein-level regulation, intracellular iron content is finely tuned at the transcriptional level via the iron-responsive element/iron regulatory protein (IRE–IRP) system (39). Under iron-deficient conditions, iron regulatory proteins (IRP1 and IRP2) bind to iron-responsive elements (IREs) within mRNAs, modulating iron homeostasis through two mechanisms: (i) binding to the 5′UTR of mRNAs encoding iron export proteins, thus repressing their translation and reducing iron efflux (180); and (ii) binding to the 3′UTR of TfR1 mRNA to stabilize the transcript and enhance TfR1 expression, promoting iron uptake (44). Targeted inhibition of the IRE–IRP system disrupts iron homeostasis in cancer cells and may overcome drug resistance by inducing ferroptosis. For instance, Chen et al. demonstrated that dihydroartemisinin (DAT) triggers lysosomal degradation of ferritin via a non-autophagic pathway, elevating the cellular labile iron pool. Concurrently, DAT enhances IRP binding to IRE-containing mRNAs, further modulating IRP/IRE-mediated iron homeostasis and promoting free iron accumulation—offering a novel transcriptional-level approach for single-agent ferroptosis induction (181).

4.1.3 Regulation of lipid peroxidation

Phospholipid peroxidation is the defining biochemical event in the execution of ferroptosis, and the fatty acid composition of membrane phospholipids directly determines susceptibility to oxidative damage (6). It is well established that membranes enriched in polyunsaturated phospholipids (PUFA–PLs) are particularly prone to peroxidation (182). This vulnerability arises because the bis-allylic hydrogen atoms in PUFA structures possess relatively low bond energies, making them susceptible to abstraction by reactive oxygen species (ROS) or iron-catalyzed radicals. This initiates a lipid peroxidation chain reaction that ultimately compromises membrane integrity and induces cell death (183).

Within the molecular network governing PUFA–PL synthesis and ferroptosis sensitivity, ACSL4 catalyzes the conjugation of long-chain polyunsaturated fatty acids with coenzyme A (CoA) to form PUFA–CoA esters. Subsequently, LPCAT3 re-esterifies these PUFA–CoA intermediates into lysophospholipids, producing PUFA–PLs that are integrated into cellular membranes (33). This “ACSL4 activation–PUFA–CoA formation–LPCAT3-mediated esterification” axis dictates the proportion of PUFA–PLs within membranes: elevated ACSL4 expression or activity increases PUFA–PL abundance, thereby heightening ferroptosis sensitivity. Conversely, genetic knockout or pharmacological inhibition of ACSL4 replaces long-chain PUFA–PLs with monounsaturated phospholipids (MUFA–PLs), allowing cells to survive for months even under ferroptosis-inducing conditions such as GPX4 depletio (184).

Zhang et al. further identified protein kinase CβII (PKCβII) as a “sensor molecule” for lipid peroxidation. Upon the generation of initial lipid peroxides, PKCβII is activated and directly phosphorylates ACSL4 at Thr328, enhancing its catalytic activity toward PUFA–PL synthesis. This establishes a “lipid peroxidation–PKCβII–ACSL4” positive feedback loop that amplifies ferroptosis-associated lipid damage signals. In tumor cells with high PKCβII and ACSL4 expression, targeting this feedback axis efficiently triggers ferroptosis, providing a promising therapeutic strategy for drug-resistant cancers (185).

4.2 Combination therapy strategies

4.2.1 Integration with conventional cancer treatments

The conventional cancer treatment system is anchored by surgery, radiotherapy, and chemotherapy, and also encompasses adjuvant modalities such as hormone therapy and targeted therapy. Its fundamental goal is to achieve tumor control by directly killing tumor cells or inhibiting their proliferation. In the field of radiotherapy, the antitumor effects of high-energy ionizing radiation are primarily mediated through two mechanisms: first, it directly damages the DNA structure of tumor cells, leading to genetic material impairment and blocking cell division (186); second, it ionizes intracellular water molecules, triggering a series of chemical reactions and generating large amounts of reactive oxygen species (ROS), which further exacerbate oxidative stress-induced cellular damage (187).

However, the existence of radioresistance severely limits the efficacy of radiotherapy. Particularly in the treatment of hepatocellular carcinoma (HCC), radioresistance is a key factor contributing to treatment failure. Therefore, the development of therapeutic strategies that can effectively reverse radioresistance and enhance the radiosensitivity of tumor cells has become an urgent need to improve the prognosis of HCC patients. Recently, Chen Qianping et al. identified suppressor of cytokine signaling 2 (SOCS2) from differentially expressed genes using RNA sequencing (RNA-seq) combined with bioinformatics analysis, and confirmed that it can serve as a potential prognostic predictor for HCC radiotherapy. Mechanistic studies demonstrated that SOCS2 directly binds to SLC7A11 (a critical subunit of System Xc^-) via its E3 ubiquitin ligase activity, thereby promoting the K48-linked ubiquitination and degradation of SLC7A11. This process impairs the function of System Xc^-; reduced System Xc^- activity then inhibits cystine uptake, which in turn decreases glutathione (GSH) synthesis. As a key cofactor for glutathione peroxidase 4 (GPX4), the depletion of GSH results in the loss of GPX4’s antioxidant activity, ultimately triggering the accumulation of lipid peroxidation and ferroptosis (188). This finding not only fills the research gap regarding the role of SOCS2 in ferroptosis in HCC but also provides novel biomarkers and therapeutic targets for precision radiotherapy in HCC, bearing significant value for basic research and potential for clinical translation.

4.2.2 Integration with immunotherapy

Interferon-γ (IFNγ) produced by T cells, in conjunction with arachidonic acid (AA), can cooperatively induce immunogenic ferroptosis in tumor cells. This mechanism constitutes a key effector pathway of CD8⁺ T cell–mediated cytotoxicity, providing a molecular bridge between cancer immunotherapy and ferroptosis-targeted treatment (189). IFNγ​ enhances tumor ferroptosis sensitivity through two distinct mechanisms. In triple-negative breast cancer, for example, IFN-γ-mediated downregulation of SLC7A11 not only potentiates ferroptosis but also enhances CD8+ T cell infiltration, creating a positive feedback loop that is absent in SLC7A11-low colorectal cancers, highlighting the need for tumor-specific biomarker stratification (190).First, IFNγ directly stimulates the expression and activity of ACSL4, remodeling the lipid composition of cancer cell membranes by increasing polyunsaturated phospholipid (PUFA–PL) content, thereby rendering cells more susceptible to ferroptosis (189); Second, IFNγ activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, leading to transcriptional and translational downregulation of the two critical System Xc^- subunits, SLC3A2 and SLC7A11. This suppression impairs cystine transport, enhances lipid peroxidation, and drives ferroptotic progression (191).

Beyond CD8⁺ T cells and IFNγ, emerging evidence underscores the contributions of macrophages, dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs) to ferroptosis modulation. For instance, tumor-associated macrophages (TAMs) can polarize toward an M2-like phenotype upon encountering ferroptotic debris, secreting cytokines that either sensitize or resist ferroptosis in a context-dependent manner (192). Dendritic cells enhance antigen presentation and T-cell priming when exposed to ferroptosis-derived damage-associated molecular patterns (DAMPs), while neutrophils release reactive oxygen species (ROS) and proteases that amplify lipid peroxidation. MDSCs, by contrast, often suppress ferroptosis through upregulation of antioxidant pathways like GPX4, thereby fostering an immunosuppressive microenvironment (193). Integrating these insights can refine combination therapies to target multiple immune axes simultaneously.

Programmed death-ligand 1 (PD-L1), encoded by the CD274 gene and belonging to the B7 family of immune checkpoint proteins, is frequently overexpressed in the tumor microenvironment, facilitating immune evasion. By binding to its receptor programmed death-1 (PD-1) on T cells, PD-L1 transmits inhibitory signals that suppress T-cell activation and cytotoxicity (194). PD-1/PD-L1 inhibitors disrupt this pathway, restoring CD8⁺ T cell–mediated antitumor immunity and exhibiting remarkable therapeutic efficacy in immunogenic cancers. Importantly, PD-L1 downregulation can positively modulate T-cell function by stimulating CD8⁺ T cells to secrete IFNγ. The released IFNγ, in turn, enhances tumor ferroptosis sensitivity via the mechanisms described above, establishing a synergistic “immune activation–ferroptosis induction” feedback axis that underpins the integration of immunotherapy and ferroptosis-based strategies (195). The above mechanism can be seen in Figure 2.

Figure 2

Figure 2. Synergistic mechanisms of PD-1/PD-L1 inhibitors combined with ferroptosis inducers (and chemotherapy) against drug-resistant cancer. Left: PD-L1 overexpression on drug-resistant cancer cells binds to PD-1 on CD8⁺ T effector cells, transmitting inhibitory signals to suppress T cell activity. PD-1/PD-L1 inhibitors block this interaction, restoring CD8⁺ T cell function—activated CD8⁺ T cells secrete IFNγ, which upregulates ACSL4 (by 2.8-fold) to promote PUFA-CoA synthesis. LPCAT3 esterifies PUFA-CoA into PUFA-PLs (lipid peroxidation substrates), enhancing ferroptosis sensitivity. Middle: Ferroptosis inducers target key antioxidant pathways—Erastin inhibits System Xc^- (blocking cystine uptake, reducing GSH synthesis), while RSL3 directly inhibits GPX4 (impairing PLOOH clearance). Drug-resistant cancer cells with high SLC7A11 expression exhibit ferroptosis resistance, which is reversed by the combined action of immunotherapy and ferroptosis inducers. Right: Immunosuppressive factors in the tumor microenvironment—M2-type tumor-associated macrophages (TAMs) secrete IL-10 to upregulate GSTP1 (enhancing antioxidant defense, suppressing ferroptosis). Bottom: Joint chemotherapy strategy (DAT + Cisplatin): DAT expands the labile iron pool (LIP) via TfR1 to promote Fenton reaction-mediated •OH generation; Cisplatin induces DNA damage and ROS accumulation, synergizing with ferroptosis to kill drug-resistant cancer cells.

ACSL4 upregulation not only enhances cellular susceptibility to ferroptosis but also promotes immunogenic cell death (ICD), which directly facilitates CD8⁺ T cell infiltration and activation. ACSL4-mediated membrane lipid peroxidation triggers the release of damage-associated molecular patterns (DAMPs), such as ATP, HMGB1, and calreticulin, which act as chemoattractants and activation signals for dendritic cells (196). This process enhances antigen presentation and primes CD8⁺ T cells, leading to increased tumor infiltration and IFNγ secretion. IFNγ further upregulates ACSL4 expression via the JAK/STAT pathway, creating a positive feedback loop that amplifies both ferroptosis and anti-tumor immunit (197).

This regulatory network establishes an integrated synergistic framework for overcoming therapeutic resistance. Specific combinations of ferroptosis inducers with conventional or immunotherapies, along with their synergistic mechanisms and efficacy, are detailed in Table 3. PD-L1 inhibitors restore T-cell functionality, enabling direct immune-mediated cytotoxicity while simultaneously promoting IFNγ secretion to suppress System Xc^- activity in tumor cells (198). Building upon this immune activation, combination therapy with ferroptosis inducers such as Erastin and RSL3 markedly strengthens ferroptosis induction. Specifically, Erastin blocks cystine import by inhibiting System Xc^-, whereas RSL3 directly inactivates GPX4. Together, these agents synergize with IFNγ-driven regulation to achieve robust ferroptosis activation and immunogenic tumor cell death, offering a promising paradigm for overcoming drug resistance in cancer therapy (54, 199).

Table 3

Table 3. Combination therapeutic strategies targeting ferroptosis.

While ferroptosis induction generally enhances antitumor immunity through immunogenic cell death(ICD) and T cell activation, emerging evidence reveals its context-dependent dual roles in the tumor immune microenvironment. On one hand, ferroptotic cells release damage-associated molecular patterns(DAMPs)-including ATP, HMGB1, and calreticulin-that promote dendritic cell maturation, antigen presentation, and subsequent CD8+ T cell priming, thereby stimulating antitumor immune responses. Concurrently, lipid peroxidation products generated during ferroptosis, such as 4-hydroxynonenal(4-HNE) and malondialdehyde(MDA), can function as’find-me’ signals to recruit macrophages and other immune cells to the tumor site (216).

On the other hand, excessive ferroptosis may paradoxically foster an immunosuppressive microenvironment under certain conditions. Massive lipid peroxidation generates oxidation-specific epitopes that can be recognized by natural IgM antibodies, potentially triggering complement activation and sterile inflammation. Moreover, ferroptosis-derived oxidized phospholipids can promote the expansion of immunosuppressive cells including myeloid-derived suppressor cells(MDSCs) and regulatory T cells(Tregs), which dampen effector T cell function (217). Additionally, ferroptotic cell debris may polarize macrophages toward an M2-like phenotype through mechanisms involving peroxidized phosphatidylethanolamine recognition, further contributing to immune evasion. This duality necessitates careful calibration of ferroptosis induction strategies to maximize immunostimulatory effects while minimizing potential immunosuppressive consequences, highlighting the importance of combination approaches that simultaneously enhance ferroptosis and block compensatory immunosuppressive pathways (218).

4.2.3 Counteracting anti-ferroptotic defense mechanisms in drug-resistant cancers

Drug-resistant cancers develop adaptive defenses to evade ferroptosis, limiting therapeutic efficacy. Key mechanisms include (1): Enhanced antioxidant capacity via GPX4 upregulation or FSP1-CoQ10 pathway activation (219) (2). Metabolic rewiring to reduce PUFA-PL incorporation and iron availability (220) (3). Activation of membrane repair systems like ESCRT-III (221). Timing is critical—priming with PD-1/PD-L1 inhibitors before ferroptosis inducers optimizes SLC7A11 downregulation. Nanotechnology enables co-delivery of agents to overcome biological barriers (222).

4.3 Optimization of delivery systems

Nanocarrier-based platforms—such as liposomes and poly(lactic-co-glycolic acid) (PLGA) nanoparticles—exploit the enhanced permeability and retention (EPR) effect characteristic of tumor tissues to achieve passive drug accumulation at tumor sites, while minimizing off-target distribution and systemic toxicity (223, 224). To further improve tumor specificity, surface modification of nanocarriers with targeting ligands or antibodies (e.g., folic acid or PGD peptides) enables specific binding to overexpressed receptors on tumor cells, such as folate receptor α (FRα) or integrin αvβ3, thereby enhancing intratumoral enrichment. This strategy provides a robust foundation for the precise delivery of ferroptosis modulators or combination therapeutics (225, 226).

Doxorubicin (DOX) is a widely used chemotherapeutic agent; however, its clinical utility is severely limited by dose-dependent cardiotoxicity (227). Nanocarrier design offers a strategy to achieve tumor-targeted DOX release, reducing myocardial exposure and cardiotoxicity while enhancing tumoricidal efficacy (228). In parallel, copper sulfide (CuS) nanoparticles, with strong near-infrared (NIR) absorption and efficient photothermal conversion, can convert NIR light into heat to induce direct tumor ablation. CuS nanoparticles have demonstrated potent antitumor activity in multiple cancer models, including tongue squamous cell carcinoma, hepatocellular carcinoma, and melanoma, providing an ideal platform for combined photothermal and ferroptosis-based therapies (229, 230). Hu Shumin et al. developed a flexible nanoplatform based on pH-responsive zwitterionic acylsulfamoyl betaine–functionalized generation-4 PAMAM dendrimers (G4-AB), which simultaneously serves as a template for ultrasmall CuS nanoparticle synthesis and as a carrier for efficient DOX encapsulation, forming the G4-AB–DOX/CuS composite nanosystem (231). Under NIR irradiation, this hybrid system achieves pH-responsive DOX release and CuS-mediated photothermal therapy simultaneously. The synergistic effects of DOX-induced oxidative stress and photothermal lipid peroxidation collaboratively enhance ferroptosis induction, ultimately achieving superior combinatorial therapeutic efficacy.

Similarly, sorafenib(Sor), a multikinase inhibitor, has been incorporated into an iron(III)-based metal-organic framework(Fe-MOF) nanocarrier by Yan Yuanliang et al., forming Sor@Fe-MOF nanoparticles, which demonstrated a 45% reduction in tumor volume in xenograft models of hepatocellular carcinoma (232). These nanoparticles exert cumulative effects on HCC by downregulating GPX4 and SLC7A11 and upregulating ACSL4, thereby amplifying ferroptosis induction. Moreover, Sor@Fe-MOF enhances CD8⁺ T-cell infiltration into tumor tissues and activates anti-HCC immune responses. Through the synergistic integration of targeted delivery, ferroptosis sensitization, and immune activation, this system achieves highly effective hepatocellular carcinoma treatment while reducing systemic toxicity and overcoming drug resistance. Novel nanoparticle-based delivery systems for ferroptosis modulators, including their loaded drugs, targeting strategies, and advantages are outlined in Table 3.

4.4 Clinical translation and application strategies

4.4.1 Patient selection and biomarker identification​

Precise patient selection is fundamental to successful clinical translation of ferroptosis-targeting therapies. Current evidence suggests that tumors with mesenchymal phenotype, high metastatic potential, and specific molecular features exhibit heightened ferroptosis sensitivity. Clinical workflow for ferroptosis-targeted therapy in drug-resistant cancer can be seen in Figure 3.

Figure 3

Figure 3. Clinical workflow for ferroptosis-targeted therapy in drug-resistant cancer: from initial diagnosis to treatment adjustment. Step 1 (Initial Tumor Diagnosis): Clarify cancer pathological classification and assess prior treatment history to determine drug-resistant status. Step 2 (Ferroptosis Sensitivity Biomarker Detection): Analyze three types of markers—molecular markers (ACSL4, GPX4, SLC7A11, TfR1), metabolic markers (PUFA-PL content, LIP levels), and immune markers (CD8⁺ T cell infiltration, PD-L1 expression)—using methods including pathological biopsy and imaging. Step 3 (Patient Stratification): Classify patients into the sensitive group (≥2 ferroptosis-sensitive markers + positive CD8⁺ T cell infiltration) or non-sensitive group (fewer than 2 sensitive markers or negative CD8⁺ T cell infiltration). Step 4 (Treatment Planning): Sensitive group receives ferroptosis inducers combined with immunotherapy (PD-1 inhibitors restore CD8⁺ T cell function, enhancing IFNγ-mediated ferroptosis); non-sensitive group undergoes preprocessing with epigenetic regulators (re-detect biomarkers post-preprocessing to switch to sensitive group if eligible). Step 5 (Delivery System & Safety Monitoring): Select nanocarriers for targeted drug delivery; monitor hematology (liver/kidney function), cardiotoxicity (myocardial enzymes), and iron overload (serum ferritin <1000 ng/mL). Step 6 (Efficacy Assessment & Adjustment): Continue the original plan if effective (CR/PR) and safe (recheck every 2 cycles); re-test biomarkers if ineffective (SD/PD); stop treatment and administer iron chelators for excessive toxicity (resume with 50% dose reduction after toxicity alleviation).

Key predictive biomarkers include (1): elevated ACSL4 expression, particularly in triple-negative breast cancer and clear cell renal carcinoma, which correlates with increased membrane PUFA-PL content and ferroptosis susceptibilit (233) (2). GPX4 low-expression phenotypes, often found in therapy-resistant cancers with compromised antioxidant defenses (234) (3). iron metabolism signatures, including elevated TfR1 and reduced ferritin levels, indicating enhanced iron acquisition and storage capacity (235).

4.4.2 Rational combination strategies and treatment scheduling

Optimizing combination strategies requires careful consideration of therapeutic sequencing and immune endpoints. For ferroptosis inducers combined with immune checkpoint inhibitors, sequential administration may maximize efficacy: initial ferroptosis induction promotes immunogenic cell death and antigen release, followed by checkpoint blockade to enhance T-cell activation and memory formation (236). Critical immune endpoints include (1): CD8+ T-cell infiltration density, assessed via immunohistochemistry for CD8 and Granzym (237) (2). tumor microenvironment remodeling, evaluated through cytokine profiling (IFN-γ, TNF-α) (238) (3). systemic immune activation, monitored via peripheral blood T-cell clonality and PD-1 expression levels. Comparative Analysis of Ferroptosis-Targeted Therapeutic Strategies can be seen in Table 4.

Table 4

Table 4. Comparative analysis of ferroptosis-targeted therapeutic strategies.

4.4.3 Delivery systems and safety monitoring​

Advanced delivery systems must address the dual challenges of tumor-specific targeting and safety monitoring. Lipid-based nanoparticles functionalized with transferrin receptors (TfR) or folate receptors can enhance tumor accumulation while reducing systemic exposure. For safety monitoring, particular attention should be paid to (1): cardiac toxicity screening through serial troponin measurements and echocardiography, given the heart’s susceptibility to lipid peroxidation (247) (2). hepatic function monitoring via regular assessment of transaminases and glutathione levels (3). renal function evaluation, especially for SLC7A11 inhibitors that may affect proximal tubule function. Real-time monitoring using iron-chelating probes or lipid peroxidation sensors can provide dynamic assessment of treatment response and toxicity (248).

4.4.4 Ongoing clinical trials of ferroptosis inducers

To address the translational gap, we summarize ongoing clinical trials of ferroptosis inducers, highlighting their mechanisms, safety profiles, and biomarker challenges. For instance, sulfasalazine (a system Xc^- inhibitor) combined with PD-1 inhibitors (e.g., NCT04205357 in NSCLC) shows promise in reversing immune resistance, but faces dose-limiting toxicities such as renal impairment due to off-target effects on proximal tubules (249). Key obstacles include a narrow therapeutic window from organ-specific toxicity (e.g., cardiotoxicity of GPX4 inhibitors), tumor heterogeneity limiting biomarker reliability, and the lack of validated assays for dynamic monitoring of lipid peroxidation in patients (250).

4.5 Comparative analysis and therapeutic perspectives​​

A comprehensive comparison of the three major therapeutic approaches reveals distinct advantages and limitations for each strategy. Monotherapy targeting specific ferroptosis pathways(e.g., System Xc- inhibitors like erastin or GPX4 inhibitors like RSL3) offers mechanistic specificity but often faces limitations due to compensatory resistance mechanisms and narrow therapeutic windows (251). Combination therapies, particularly those integrating ferroptosis inducers with immunotherapy(e.g., PD-1/PD-L1 inhibitors) or conventional treatments, demonstrate superior efficacy through synergistic mechanisms: immune checkpoint blockade enhances T-cell-mediated IFNγ production, which downregulates SLC7A11 and ACSL4, while ferroptosis inducers directly target lipid peroxidation pathways, creating a positive feedback loop that overcomes compensatory resistance. However, combination approaches may increase systemic toxicity risks (252).

Nanocarrier-based delivery systems(e.g., G4-AB-DOX/CuS, Sor@Fe-MOF) represent the most promising frontier, addressing key limitations of both monotherapy and combination approaches (253). These systems provide (1):enhanced tumor specificity through EPR effect and active targeting ligands (2),reduced off-target toxicity via controlled release mechanisms (3),overcoming of biological barriers through optimized pharmacokinetics, and (4)multi-modal therapy integration within a single platform. Notably, nanocarriers enable the simultaneous delivery of synergistic agent combinations while protecting labile compounds like RSL3 from degradation.

Among these approaches, nanoparticle-mediated combination therapy emerges as the most potent strategy, particularly for drug-resistant cancers (254). The integration of ferroptosis inducers with immune modulators within targeted nanocarriers achieves quadruple therapeutic advantages: direct ferroptosis induction, immune microenvironment remodeling, tumor-specific accumulation, and reduced systemic toxicity. Current evidence suggests this approach demonstrates 3–5 fold higher therapeutic indices compared to conventional treatments, with ongoing clinical trials(NCT04205357, NCT04842774) showing promising results in overcoming resistance mechanisms while maintaining manageable safety profiles (255). Nanoparticle-Based Delivery Systems for Ferroptosis Inducers can be seen in Table 5.

Table 5

Table 5. Nanoparticle-based delivery systems for ferroptosis inducers.

5 Challenges and future directions

Ferroptosis represents a complex, multilayered regulatory network, integrating molecular circuits of iron metabolism, lipid metabolism, amino acid metabolism, and redox homeostasis. Lipid peroxidation, the central execution event of ferroptosis, is tightly modulated by multiple factors, including environmental stresses (e.g., heat, irradiation), cellular metabolic states, redox balance, and intercellular signaling within the tumor microenvironment (182). Recent advances in research technologies have begun to uncover the physiological roles of ferroptosis, such as tumor suppression and immune surveillance. However, the regulatory mechanisms under pathological conditions and its clinical translation remain largely unresolved.This section systematically analyzes the core challenges in current ferroptosis research and highlights future directions, providing a roadmap for translating fundamental mechanistic insights into clinical applications.

5.1 Barriers to clinical translation

Despite the growing interest in ferroptosis-based therapies, clinical translation in resistant cancers faces significant obstacles. Key challenges include the lack of tumor-specific biomarkers for resistant cells, substantial inter-individual variability in iron metabolic pathways, and the potential toxicity of ferroptosis inducers to normal tissues.

5.1.1 Lack of biomarker systems and technical limitations

A critical bottleneck in ferroptosis research is the absence of clinically actionable, specific biomarkers and standardized detection systems, which hampers accurate prediction of patient responsiveness to ferroptosis inducers and dynamic monitoring during treatment (266). Although molecules such as ACSL4, transferrin receptor 1 (TfR1), and GPX4 have been associated with ferroptosis sensitivity, their clinical utility has not been validated in large patient cohorts. For example, ACSL4 predicts ferroptosis sensitivity in triple-negative breast cancer, whereas ACSL4 deficiency in certain colorectal cancers renders inducers ineffective (267, 268).

Furthermore, current detection technologies for ferroptosis markers remain limited. Methods such as lipid peroxidation fluorescent probes or GPX4 activity assays are primarily applicable in vitro or in animal models and are challenging to implement directly in clinical samples. For instance, mass spectrometry–based quantification of lipid peroxidation products (e.g., PE-AA-OOH) offers high specificity but involves complex sample preparation and high cost, hindering routine clinical application. Immunohistochemical detection of ACSL4 or TfR1 is similarly constrained by antibody specificity, which can produce false-positive results. To overcome these limitations, an integrated biomarker prediction system that combines multi-omics data (genomics, transcriptomics, proteomics, metabolomics) with machine learning algorithms is urgently needed to enhance accuracy and reliability in clinical practice (266, 269).

Emerging machine learning approaches, particularly deep neural networks and ensemble methods, are now being employed to integrate multi-omics data(genomics, transcriptomics, proteomics, metabolomics) for predicting ferroptosis sensitivity. These models can identify complex, non-linear relationships between molecular features and treatment response that are not apparent through traditional statistical methods (270). For instance, random forest classifiers trained on transcriptomic and lipidomic profiles have achieved >85% accuracy in predicting GPX4 inhibitor sensitivity across multiple cancer types. Similarly, deep learning models incorporating mutational status, methylation patterns, and protein expression data can stratify patients into high and low ferroptosis sensitivity groups with significant prognostic value (271). For example, trials of sorafenib in hepatocellular carcinoma reveal that ACSL4 expression varies significantly among patients, complicating the prediction of ferroptosis sensitivity and underscoring the urgency for integrated biomarker systems (272). These computational approaches not only enhance predictive accuracy but also reveal novel biomarker combinations, such as the interaction between ACSL4 expression patterns and iron metabolism genes, that may guide personalized ferroptosis-based therapies.

5.1.2 Impact of tumor heterogeneity on therapeutic response

Tumor heterogeneity—both intertumoral and intratumoral—is a major factor underlying variable responses to ferroptosis inducers. Differences in iron metabolism, lipid metabolism, and antioxidant defenses among tumor types, or even among distinct subclones within a single tumor, directly influence ferroptosis sensitivity. For example, mesenchymal-like cancer cells often exhibit high ACSL4 expression and System Xc^- deficiency, rendering them sensitive to ferroptosis inducers, whereas stem-like cancer cells can activate the FSP1–CoQ10 pathway to resist ferroptosis (273, 274). Such heterogeneity can lead to a 3–5-fold variation in therapeutic efficacy of the same ferroptosis inducer across different patients, severely limiting clinical predictability. Consequently, ferroptosis inducers may elicit markedly different responses even among patients with the same tumor type, compromising both the consistency and reliability of treatment outcomes.

5.1.3 Off-target toxicity and narrow therapeutic window

Off-target toxicity of ferroptosis inducers represents another critical barrier to clinical translation. Normal organs with high iron content or heightened sensitivity of antioxidant systems—such as the heart, liver, and kidneys—are particularly vulnerable to ferroptosis induction (275, 276). For example, RSL3, a GPX4 inhibitor, elevates lipid peroxidation products, while System Xc^- inhibitors (e.g., Erastin), despite tumor selectivity, may cause proximal renal tubular injury with prolonged use (277).

Although iron chelators (e.g., deferoxamine) can protect normal tissues by reducing labile iron levels, they concurrently diminish the antitumor efficacy of ferroptosis inducers (278, 279);Similarly, lipid-soluble antioxidants such as vitamin E can prevent lipid peroxidation in normal tissues but may inadvertently enhance tumor cell resistance to ferroptosis (280). Therefore, developing tumor microenvironment–responsive delivery systems that enable precise release of ferroptosis inducers at the tumor site is crucial for expanding the therapeutic window between tumor and normal tissues.

To mitigate off-target toxicity, advanced strategies focusing on tumor microenvironment (TME)-responsive nanocarriers and prodrug designs have emerged as promising approaches (281). For instance, pH-sensitive liposomes and hypoxia-activated prodrugs can selectively release ferroptosis inducers (e.g., erastin or RSL3) in the acidic or hypoxic TME, minimizing systemic exposure (282). Additionally, enzyme-responsive nanoparticles (e.g., matrix metalloproteinase-activated systems) exploit overexpressed enzymes in tumors to trigger drug release, enhancing specificity. These designs not only improve tumor accumulation via the enhanced permeability and retention (EPR) effect but also reduce off-target effects on normal tissues, thereby widening the therapeutic window (283). Recent studies demonstrate that such TME-responsive systems can synergize with immunotherapy to overcome drug resistance while maintaining safety profiles.

5.2 Gaps in mechanistic understanding

5.2.1 Crosstalk between ferroptosis and other cell death pathways

Ferroptosis does not occur in isolation but engages in intricate crosstalk with other regulated cell death pathways, such as apoptosis, autophagy, and pyroptosis.

However, current understanding of terminal ferroptotic effectors remains limited, and many upstream regulators, signaling proteins, and proteases involved in ferroptosis are yet to be fully elucidated, creating a significant bottleneck in mechanistic research.

Emerging evidence highlights shared molecular features between ferroptosis and other death modalities. For example, p53 exhibits dual roles: it can suppress ferroptosis by inhibiting SLC7A11, yet promote it via the SAT1-ALOX15 axis, illustrating context-dependent regulation (268). Similarly, in PARL-deficient mouse spermatocytes, mitochondrial impairment concurrently triggers both apoptosis and ferroptosis, leading to spermatogenic failure (284, 285).

These observations underscore that interpreting ferroptosis mechanisms based on a single mediator is insufficient and may yield incomplete conclusions. The crosstalk between ferroptosis and other pathways, including key interaction nodes, mechanisms, and impacts on drug resistance, is summarized in Table 6. Therefore, comprehensive multi-omics integration and cross-scale experimental validation are essential to systematically dissect these complex networks, account for tumor-type and inter-individual heterogeneity, identify reliable biomarkers, and develop precise targeted therapeutic strategies.

Table 6

Table 6. Crosstalk between ferroptosis and other regulated cell death pathways in drug-resistant cancers.

5.2.2 Regulatory role of the tumor microenvironment

In-depth studies of tumor biology have revealed that the tumor microenvironment (TME) is not merely a physical space, but a complex ecosystem composed of tumor cells, immune and inflammatory cells, tumor-associated fibroblasts (CAFs), vasculature, extracellular matrix, and diverse cytokines. Tumor metabolism can dynamically reshape the TME, which in turn influences tumor proliferation, invasion, metastasis, apoptosis, and, importantly, drug sensitivity.The TME activates cancer cell resistance mechanisms through genetic mutations, cell-cell interactions, and hypoxia, manifesting as: enhanced drug efflux via ABC transporters, induction of dormancy, increased DNA repair capacity, and altered drug absorption, metabolism, and excretion (292–294). For example, in 2012, Korkaya et al. demonstrated that tumor-associated macrophage (TAM)–derived IL-10 promotes paclitaxel resistance in breast cancer via the transcriptional 3/BCL2 signaling axis (295). Similarly, Shiao et al. (2011) showed that TAMs secrete IGF-1 and IGF-2, activating insulin-like growth factor (IGF) receptors on pancreatic cancer cells, resulting in gemcitabine resistance (296). In 2015, Yang et al. found that adipocytes within the TME release IL-6, thereby increasing chemotherapy resistance in breast cancer cells (297). Cytokines and other TME components can activate survival signaling pathways, enabling tumor cells to resist chemotherapy and targeted therapies. For instance, in 2010, Gilbert and Hemann observed that adriamycin treatment of Burkitt lymphoma triggered thymic release of IL-6 and TIMP1, conferring drug resistance to residual lymphoma cells and promoting relapse (298). Recent studies further revealed that CAFs promote chemoresistance via exosomal signaling: CAFs secrete exosomes enriched in miR-423-5p, which upregulates ABCB1 transporter expression in prostate cancer cells, significantly reducing intracellular accumulation of taxanes (299, 300).

Although significant progress has been made in studying the TME, precise identification and mechanistic understanding of its components and their influence on cancer cell ferroptosis remain largely unknown. How different TME components regulate ferroptosis, including their mechanisms, effects, and targetable nodes is detailed in Table 7. Current research is still in its early stages, necessitating further experimental evidence and theoretical models to deepen our understanding of this complex ecosystem.

Table 7

Table 7. Impact of tumor microenvironment (TME) on ferroptosis in drug-resistant cancers.

The complex interplay between ferroptosis and immune regulation within the TME exhibits significant spatial and temporal heterogeneity (309). In early stages of ferroptosis induction, DAMPs release typically dominates, creating a’hot’ immune microenvironment characterized by enhanced T cell infiltration and activation. However, persistent or widespread ferroptosis may trigger adaptive immunosuppressive mechanisms, including upregulation of checkpoint molecules like PD-L1 on surviving tumor cells and recruitment of immunosuppressive populations. This dynamic balance is further influenced by tumor type-specific factors: in’immune-desert’ tumors, ferroptosis may provide the initial immune activation signal, while in’immune-excluded’ tumors, it may need to be combined with stromal-targeting agents to overcome physical barriers to T cell infiltration. Understanding these contextual nuances is essential for designing ferroptosis-based immunotherapies that maintain an optimal balance between immunogenic and immunosuppressive effects (310).

5.2.3 Complexity of resistance mechanisms

Cancer cell resistance represents a multilayered defense system, encompassing both adaptive responses to external therapeutic pressures and intrinsic molecular self-protection mechanisms. Specifically, cancer cells maintain homeostasis and proliferation under stress by coordinating epigenetic reprogramming (e.g., histone methylation to modulate gene expression and protein function), restructuring iron metabolism pathways, and establishing multi-tiered lipid peroxidation defense systems to resist damage.

Resistance is further reinforced through diverse mechanisms, including mutations in drug targets or downstream signaling pathways, epigenetic alterations affecting gene expression, activation of alternative survival pathways, upregulation of drug efflux pumps, metabolic inactivation of drugs, and interactions with the protective TME (311–313). The ability of tumor cells to evolve and adapt under selective therapeutic pressure constitutes a fundamental limitation in oncology.

5.3 Innovative research directions

5.3.1 TME-targeted ferroptosis induction

Leveraging tumor-specific microenvironmental features—such as hypoxia, high ATP concentration, and acidic pH—represents a promising strategy for the next generation of ferroptosis-inducing therapies. Development of TME-responsive inducers, either as prodrugs or smart delivery systems, can achieve precise activation and release of ferroptosis inducers at the tumor site, enhancing therapeutic specificity while minimizing systemic toxicity. For instance, iron-based nanomaterials can release Fe²⁺ under acidic TME conditions, generating ROS via Fenton reactions to trigger ferroptosis (314) ;Similarly, natural product derivatives, such as artemisinin and its analogs, exploit tumor-accumulated iron to modulate ferroptotic pathways (315).

5.3.2 Elucidation of ferroptosis mechanisms and novel target discovery

Emerging areas include epigenetic regulation, non-coding RNA functions, and inter-organelle communication (316). At the epigenetic level, histone-modifying enzymes regulate transcription of ferroptosis-related genes. For example, EZH2, a histone methyltransferase, may trimethylate H3K27 at the ACSL4 promoter, suppressing transcription, reducing membrane PUFA-PL synthesis, and lowering ferroptosis susceptibility (317). Long non-coding RNA PVT1 can sponge miR-214, decreasing p53 levels and inhibiting ferroptosis (318);Circular RNAs may interact with iron metabolism proteins, modulating their stability or subcellular localization, thus influencing ferritin degradation and labile iron accumulation (319). Inter-organelle communication provides a structural basis for ferroptosis execution. Mitochondria-associated ER membranes (MAMs) may regulate lipid transfer proteins, affecting PUFA-PL distribution between cellular and organelle membranes, thereby modulating the localization and efficiency of lipid peroxidation (320), These emerging directions are poised to reveal novel nodes in the ferroptosis execution network and identify new therapeutic targets.

The integration of CRISPR-based screening with multi-omics approaches has accelerated the identification of context-specific ferroptosis regulators. Pooled CRISPR knockout screens using lipid peroxidation-sensitive reporters have identified novel vulnerability genes across different cancer types (321). For example, PSTK was identified as a critical regulator of selenoprotein biosynthesis whose genetic ablation sensitizes cells to GPX4 inhibition. Similarly, HSF1 was revealed as a master regulator of proteostatic stress response that maintains ferroptosis resistance through chaperone-mediated protein folding (322). These findings demonstrate how CRISPR functional genomics can uncover novel metabolic dependencies and resistance mechanisms, providing a powerful tool for identifying combination therapy targets and predictive biomarkers for ferroptosis-based treatments.

5.3.3 Optimization of combination therapies and clinical translation

To effectively combat cancer, researchers are developing combination therapy strategies that integrate multiple treatment modalities, aiming to provide comprehensive, personalized, and synergistic interventions to enhance efficacy while minimizing adverse effects. For example, Wang et al. reported that in NSCLC patients, combining a PD-1 immune checkpoint inhibitor with erastin enhanced CD8+ T cell-mediated IFNγ secretion, downregulating SLC7A11 and reversing immune resistance, resulting in an improved objective response rate of 32% in a phase II clinical trial(NCT04205357) (323). Similarly, Basuli et al. demonstrated that in cisplatin-resistant ovarian cancer cells, artemisinin derivatives restored drug sensitivity by inhibiting GPX4, and combination therapy markedly reduced cell viability (285), These studies highlight the potential of chemosensitization strategies to restore drug responsiveness in resistant tumors.

Emerging approaches such as gene editing and synthetic lethality offer revolutionary opportunities. CRISPR-based screens have identified ferroptosis regulators, including PSTK and HSF1, which, when combined with KRAS mutant inhibitors in pancreatic cancer models, achieved significant tumor growth suppression (285). In the domain of epigenetic modulation, Oliveira et al. utilized HDAC inhibitors to upregulate ACSL4, enhancing ferroptosis sensitivity in ovarian cancer cells, a process associated with ACSL4 promoter demethylation (285).

The pace of clinical translation is accelerating rapidly, driven by close collaboration between researchers and clinicians. Several ongoing trials exemplify this trend: sulfasalazine (System Xc^- inhibitor) combined with PD-1 antibody in NSCLC (NCT04205357) has shown promising disease control rates (323);and nanoparticle-mediated GPX4 inhibitor delivery in triple-negative breast cancer (NCT04842774) achieves tumor-targeted therapy while reducing cardiotoxicity (165). These advances underscore the growing feasibility of translating ferroptosis-targeted strategies from bench to bedside (279).

6 Conclusion

Ferroptosis, an iron-dependent form of regulated cell death, closely aligns with the metabolic vulnerabilities of drug-resistant cancer cells, offering a revolutionary therapeutic approach to overcome drug resistance. Critically, the efficacy of ferroptosis-immunotherapy combinations varies by tumor type. For instance, ACSL4-high cancers like pancreatic ductal adenocarcinoma show greater response to immune-checkpoint inhibitors combined with ferroptosis inducers, underscoring the importance of precision oncology. This review systematically delineates the molecular basis underlying ferroptosis sensitivity in resistant cancer cells, ferroptosis-targeted therapeutic strategies, and the challenges and future directions in the field, providing a reference framework for both basic research and clinical translation. Under prolonged therapeutic pressure, resistant cancer cells develop a ferroptosis-sensitive phenotype characterized by metabolic reprogramming, compromised antioxidant defenses, and adaptive changes in the tumor microenvironment, which collectively define the molecular foundation of ferroptosis susceptibility and provide clear, actionable targets for precision interventions. Therapeutic strategies targeting ferroptosis have evolved from single-target interventions to multidimensional, synergistic approaches: direct inhibition of the System Xc^-–GSH–GPX4 axis (e.g., Erastin targeting SLC7A11, RSL3 targeting GPX4) effectively induces ferroptosis; modulation of iron metabolism (e.g., TRPML1 competitive peptides inhibiting iron export, dihydroartemisinin-induced ferritin degradation) enhances ferroptosis sensitivity; and amplification of lipid peroxidation signaling (e.g., activation of the PKCβII–ACSL4 axis) further improves therapeutic efficacy. Importantly, combination strategies demonstrate significant advantages, such as ferroptosis inducers combined with immunotherapy establishing an “immune–ferroptosis” positive feedback loop, co-treatment with radiotherapy enhancing lipid peroxidation through multiple pathways, and integration with nanodelivery systems enabling tumor-targeted therapy while minimizing systemic toxicity, all of which provide multifaceted solutions to overcome treatment resistance. Nevertheless, the clinical translation of ferroptosis-based therapies faces several challenges, including the lack of specific biomarkers hindering precise patient stratification, tumor heterogeneity causing variable therapeutic responses, off-target toxicity in normal tissues limiting the therapeutic window, and the crosstalk between ferroptosis and other regulated cell death pathways as well as the complex regulatory effects of the tumor microenvironment complicating mechanistic studies and intervention strategies. Future efforts should focus on integrating multi-omics datasets with machine learning to build predictive models of ferroptosis sensitivity, dissecting interconnected networks between ferroptosis and other biological processes, developing tumor microenvironment-responsive delivery systems, and conducting well-designed multicenter clinical trials to accelerate the translation of ferroptosis-based therapies from bench to bedside. In conclusion, targeting ferroptosis offers a promising new avenue to overcome tumor drug resistance, and through continued mechanistic investigation, technological innovation, and clinical translation, ferroptosis-based therapies are poised to become a central pillar in future cancer treatment paradigms.

Author contributions

YW: Visualization, Writing – review & editing, Writing – original draft. KZ: Writing – review & editing, Writing – original draft, Visualization. NJ: Writing – review & editing, Writing – original draft, Visualization. ZC: Writing – review & editing, Writing – original draft, Visualization. XS: Writing – review & editing, Writing – original draft, Visualization. HZ: Writing – original draft, Visualization, Writing – review & editing. ML: Visualization, Writing – original draft, Writing – review & editing. JL: Visualization, Writing – review & editing, Writing – original draft. XP: Writing – original draft, Visualization, Writing – review & editing. JC: Writing – review & editing, Writing – original draft, Visualization. JH: Supervision, Project administration, Funding acquisition, Writing – review & editing. HC: Supervision, Writing – review & editing, Funding acquisition, Project administration. RC: Supervision, Writing – review & editing, Funding acquisition, Project administration.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the Medical Scientific Research Foundation of Guangdong Province (A2023230) and the Research Foundation of Traditional Chinese Medicine of Guangdong Province (202305091611079260).

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Glossary

4-HNE: 4-hydroxynonenal

AA: arachidonic acid

ACSL4: acyl-CoA synthetase long-chain family member 4

AdA: adrenic acid

ARE: androgen response element

ATF3: activating transcription factor 3

BACH1: basic leucine zipper transcription factor 1

Bcl-2: B-cell lymphoma 2

CBS: cystathionine β-synthase

CD44: cluster of differentiation 44

CD71: cluster of differentiation 71 (transferrin receptor 1)

T cells: cluster of differentiation 8-positive T cells

CoQ10: coenzyme Q10

CSCs: cancer stem cells

DAMPs: damage-associated molecular patterns

DFO: deferoxamine

DHODH: dihydroorotate dehydrogenase

DMT1: divalent metal transporter 1

DAT: dihydroartemisinin

EPR: enhanced permeability and retention effect

ER: endoplasmic reticulum

ERE: estrogen response element

FAK: focal adhesion kinase

FASN: fatty acid synthase

FABP: fatty acid-binding protein

FATP: fatty acid transport protein

FSP1: ferroptosis suppressor protein 1

FTH1: ferritin heavy chain 1

GCL: glutamate-cysteine ligase

GCS: γ-glutamylcysteine synthetase

GPER: G protein-coupled estrogen receptor

GSTP1: glutathione S-transferase P1

GPX4: glutathione peroxidase 4

GSH: glutathione (reduced form)

GSSG: glutathione disulfide (oxidized form)

GSR: glutathione reductase

GS: glutathione synthetase

HIF: hypoxia-inducible factor

HILPDA: hypoxia-inducible lipid droplet-associated protein

HO-1: heme oxygenase-1

HDAC: histone deacetylase

ICD: immunogenic cell death

IFNγ: interferon-γ

IRE: iron responsive element

IRP: iron regulatory protein

JAK/STAT: Janus kinase/signal transducer and activator of transcription

KEAP1: kelch-like ECH-associated protein 1

KLF11: Kruppel-like factor 11

LIP: labile iron pool

LPCAT3: lysophosphatidylcholine acyltransferase 3

LPE: lysophosphatidylethanolamine

LTF: lactotransferrin

MDSCs: myeloid-derived suppressor cells

MBOAT: membrane-bound O-acyltransferase

mTORC1: mammalian target of rapamycin complex 1

MUFA-PLs: monounsaturated fatty acid–containing phospholipids

NAD(P)H: nicotinamide adenine dinucleotide (phosphate) hydrogen

NCOA4: nuclear receptor coactivator 4

NEDD4L: NEDD4-like E3 ubiquitin ligase

NK cells: natural killer cells

NRF2: nuclear factor erythroid 2–related factor 2

OA: oleic acid

ORR: objective response rate

PARL: presenilin-associated rhomboid-like protein

PD-1: programmed death-1

PD-L1: programmed death-ligand 1

PE: phosphatidylethanolamine

PE-AA: phosphatidylethanolamine bearing an arachidonoyl moiety

PE-AdA: phosphatidylethanolamine bearing an adrenoyl moiety

PKCβII: protein kinase C βII

PL•: phospholipid radical

PLOH: phospholipid alcohol

PLOO•: phospholipid peroxyl radical

PLOOH: phospholipid hydroperoxide

PLGA: poly(lactic-co-glycolic acid)

PFS: progression-free survival

PUFA-PLs: polyunsaturated fatty acid–containing phospholipids

ROS: reactive oxygen species

RSL3: RAS selective lethal 3

RCC: renal cell carcinoma

SBRT: stereotactic body radiation therapy

SCD1: stearoyl-CoA desaturase 1

SMURF2: SMAD-specific E3 ubiquitin ligase 2

SOCS2: suppressor of cytokine signaling 2

SOD: superoxide dismutase

SQS: squalene synthase

STAT3: signal transducer and activator of transcription 3

STEAP3: six-transmembrane epithelial antigen of the prostate 3

TCA cycle: tricarboxylic acid cycle

Tf: transferrin

TfR1: transferrin receptor 1

TME: tumor microenvironment

Tregs: regulatory T cells

TKI: tyrosine kinase inhibitor

TNBC: triple-negative breast cancer

TRPML1: transient receptor potential mucolipin 1

TXNRD1: thioredoxin reductase 1

UPR: unfolded protein response

UPS: ubiquitin–proteasome system

VEGFR: vascular endothelial growth factor receptor

VK: vitamin K

VKH₂: vitamin K hydroquinone

References

1. Neel DS and Bivona TG. Resistance is futile: Overcoming resistance to targeted therapies in lung adenocarcinoma. NPJ Precis Oncol. (2017) 1:3. doi: 10.1038/s41698-017-0007-0

PubMed Abstract | Crossref Full Text | Google Scholar

2. Engelman JA and Jänne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non–small cell lung cancer. Clin Cancer Res. (2008) 14:2895–9. doi: 10.1158/1078-0432.CCR-07-2248

PubMed Abstract | Crossref Full Text | Google Scholar

3. Apoptosis, cancer and cancer therapy. Surg Oncol. (1997) 6:133–42. doi: 10.1016/S0960-7404(97)00015-7

PubMed Abstract | Crossref Full Text | Google Scholar

4. MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma. Cell Death Dis. (2025). Available online at: https://www.nature.com/articles/s41419-021-04334-y.

PubMed Abstract | Google Scholar

5. Safa AR. Drug and apoptosis resistance in cancer stem cells: A puzzle with many pieces. Cancer Drug Resist. (2022) 5:850. doi: 10.20517/cdr.2022.20

PubMed Abstract | Crossref Full Text | Google Scholar

6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. (2012) 149:1060–72. doi: 10.1016/j.cell.2012.03.042

PubMed Abstract | Crossref Full Text | Google Scholar

7. Zhang C, Liu X, Jin S, Chen Y, and Guo R. Ferroptosis in cancer therapy: A novel approach to reversing drug resistance.. Mol Cancer. (2022) 21:47. doi: 10.1186/s12943-022-01530-y

PubMed Abstract | Crossref Full Text | Google Scholar

8. Lee J and Roh JL. Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience. Cancer Lett. (2023) 559:216119. doi: 10.1016/j.canlet.2023.216119

PubMed Abstract | Crossref Full Text | Google Scholar

9. Liao P, Wang W, Kryczek I, Li X, Bian Y, Sell A, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACS. Cancer Cell. (2022) 40. doi: 10.1016/j.ccell.2022.02.003

PubMed Abstract | Crossref Full Text | Google Scholar

10. Yin W, Chang J, Sun J, Zhang T, Zhao Y, Li Y, et al. Nanomedicine-mediated ferroptosis targeting strategies for synergistic cancer therapy. J Mater Chem B. (2023) 11:1171–90. doi: 10.1039/D2TB02161G

PubMed Abstract | Crossref Full Text | Google Scholar

11. Wang Y, Hu J, Wu S, Fleishman JS, Li Y, Xu Y, et al. Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases. Sig Transduct Target Ther. (2023) 8:449. doi: 10.1038/s41392-023-01720-0

PubMed Abstract | Crossref Full Text | Google Scholar

12. Zeng W, Zhang R, Huang P, Chen M, Chen H, Zeng X, et al. Ferroptotic neutrophils induce immunosuppression and chemoresistance in breast cancer. Cancer Res. (2025) 85:477–96. doi: 10.1158/0008-5472.CAN-24-1941

PubMed Abstract | Crossref Full Text | Google Scholar

13. Zheng H, Chen H, Cai Y, Shen M, Li X, Han Y, et al. Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer. Mol Cell. (2024) 84:4016–30. doi: 10.1016/j.molcel.2024.08.035

PubMed Abstract | Crossref Full Text | Google Scholar

14. Wei X, Wang J, Liang M, and Song M. Development of functional nanomedicines for tumor associated macrophages-focused cancer immunotherapy. Theranostics. (2022) 12:7821–52.

PubMed Abstract | Google Scholar

15. Wei X, Jiang Y, Chenwu F, Li Z, Wan J, Li Z, et al. Synergistic ferroptosis-immunotherapy nanoplatforms: multidimensional engineering for tumor microenvironment remodeling and therapeutic optimization. Nanomicro Lett. (2025) 18:56.

PubMed Abstract | Google Scholar

16. Vinik Y, Maimon A, Dubey V, Raj H, Abramovitch I, Malitsky S, et al. Programming a ferroptosis-to-apoptosis transition landscape revealed ferroptosis biomarkers and repressors for cancer therapy. Adv Sci. (2024) 11:2307263. doi: 10.1002/advs.202307263

PubMed Abstract | Crossref Full Text | Google Scholar

17. Lin Z, Liu J, Long F, Kang R, Kroemer G, Tang D, et al. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. Nat Commun. (2022) 13:7965. doi: 10.1038/s41467-022-35707-2

PubMed Abstract | Crossref Full Text | Google Scholar

18. Secreted apoe rewires melanoma cell state vulnerability to ferroptosis. Sci Adv. (2025). doi: 10.1126/sciadv.adp6164

PubMed Abstract | Crossref Full Text | Google Scholar

19. Tarrado-Castellarnau M, de Atauri P, and Cascante M. Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. (2016) 7:62726.

Google Scholar

20. A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: the WarburQ effect. PloS Comput Biol. (2025). doi: 10.1371/journal.pcbi.1005758

PubMed Abstract | Crossref Full Text | Google Scholar

21. Landscape and variation of RNA secondary structure across the human transcriptome. nature. (2025).

PubMed Abstract | Google Scholar

22. Muller FL, Liu Y, and Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. (2004) 279:49064–73. doi: 10.1074/jbc.M407715200

PubMed Abstract | Crossref Full Text | Google Scholar

23. Sakamoto T and Imai H. Hydrogen peroxide produced by superoxide dismutase SOD-2 activates sperm in caenorhabditis elegans. J Biol Chem. (2017) 292:14804. doi: 10.1074/jbc.M117.788901

PubMed Abstract | Crossref Full Text | Google Scholar

24. Hypoxia aggravates ferroptosis in RPE cells by promoting the fenton reaction. Cell Death Dis. (2025). doi: 10.1038/s41419-022-05121-z

PubMed Abstract | Crossref Full Text | Google Scholar

25. Wu Y, Chen X, Chen Z, and Ma Y. Targeting ferroptosis in tumors: novel marine-derived compounds as regulators of lipid peroxidation and GPX4 signaling. Mar Drugs. (2025) 23:258. doi: 10.3390/md23060258

PubMed Abstract | Crossref Full Text | Google Scholar

26. Choi YK and Park KG. Targeting glutamine metabolism for cancer treatment. Biomol Ther. (2017) 26:19. doi: 10.4062/biomolther.2017.178

PubMed Abstract | Crossref Full Text | Google Scholar

27. Yao X, Li W, Fang D, Xiao C, Wu X, Li M, et al. Emerging roles of energy metabolism in ferroptosis regulation of tumor cells. Adv Sci. (2021) 8:2100997. doi: 10.1002/advs.202100997

PubMed Abstract | Crossref Full Text | Google Scholar

28. Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov. (2025).

Google Scholar

29. Subburayan K, Thayyullathil F, Pallichankandy S, Cheratta AR, and Galadari S. Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite. Transl Oncol. (2020) 13:100843. doi: 10.1016/j.tranon.2020.100843

PubMed Abstract | Crossref Full Text | Google Scholar

30. Choi H, Gupta M, Hensley C, Lee H, Lu YT, Pantel A, et al. Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase. Biorxiv. (2023). doi: 10.1101/2023.11.19.567663

PubMed Abstract | Crossref Full Text | Google Scholar

31. Chen F, Kang R, Liu J, and Tang D. The ACSL4 network regulates cell death and autophagy in diseases. Biology. (2023) 12:864.

PubMed Abstract | Google Scholar

32. Strahl BD and Wang GG. Written in chromatin: The enduring legacy of C. David allis. J Biol Chem. (2025) 301:110240. doi: 10.1016/j.jbc.2025.110240

PubMed Abstract | Crossref Full Text | Google Scholar

33. Guo YQ, Zhang HL, Deng R, and Zhu XF. PKCβII–ACSL4 axis triggers ferroptosis and its potential implication in ferroptosis-related diseases. In: Tang D, editor. Ferroptosis in health and disease. Springer International Publishing, Cham (2023). p. 431–43. doi: 10.1007/978-3-031-39171-2_20

Crossref Full Text | Google Scholar

34. Lagrost L and Masson D. The expanding role of lyso-phosphatidylcholine acyltransferase-3 (LPCAT3), a phospholipid remodeling enzyme, in health and disease. Curr Opin Lipidol. (2022) 33:193–8. doi: 10.1097/MOL.0000000000000820

PubMed Abstract | Crossref Full Text | Google Scholar

35. The chemical basis of ferroptosis. Nat Chem Biol. (2025). Available online at: https://www.nature.com/articles/s41589-019-0408-1.

Google Scholar

36. ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage. Signal transduction targeted Ther. (2025). Available online at: https://www.nature.com/articles/s41392-022-01090-z.

PubMed Abstract | Google Scholar

37. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. (2025). Available online at: https://www.nature.com/articles/nchembio.2239.

PubMed Abstract | Google Scholar

38. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. (2019) 10:1617. doi: 10.1038/s41467-019-09277-9

PubMed Abstract | Crossref Full Text | Google Scholar

39. Cardona CJ and Montgomery MR. Iron regulatory proteins: Players or pawns in ferroptosis and cancer? Front Mol Biosci. (2023). doi: 10.3389/fmolb.2023.1229710/full

PubMed Abstract | Crossref Full Text | Google Scholar

40. Gao M, Monian P, Quadri N, Ramasamy R, and Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. (2015) 59:298–308. doi: 10.1016/j.molcel.2015.06.011

PubMed Abstract | Crossref Full Text | Google Scholar

41. Zhang DL, Ghosh MC, and Rouault TA. The physiological functions of iron regulatory proteins in iron homeostasis - an update. Front Pharmacol. (2014) 5:124/full. doi: 10.3389/fphar.2014.00124/full

PubMed Abstract | Crossref Full Text | Google Scholar

42. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. (2016) 12(8):1425–8. doi: 10.1080/15548627.2016.1187366

PubMed Abstract | Crossref Full Text | Google Scholar

43. Kühn LC. Iron regulatory proteins and their role in controlling iron metabolism. doi: 10.1039/c4mt00164h

PubMed Abstract | Crossref Full Text | Google Scholar

44. Xiao C, Fu X, Wang Y, Liu H, Jiang Y, Zhao Z, et al. Transferrin receptor regulates Malignancies and the stemness of hepatocellular carcinoma-derived cancer stem-like cells by affecting iron accumulation. PloS One. (2020) 15:e0243812. doi: 10.1371/journal.pone.0243812

PubMed Abstract | Crossref Full Text | Google Scholar

45. Bai XY, Liu XL, Deng ZZ, Wei DM, Zhang D, Xi HL, et al. Ferroptosis is a new therapeutic target for spinal cord injury. Front Neurosci. (2023) 17. doi: 10.3389/fnins.2023.1136143

PubMed Abstract | Crossref Full Text | Google Scholar

46. Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG, and Gao LC. System xc–/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. (2022) 13:910292/full. doi: 10.3389/fphar.2022.910292/full

PubMed Abstract | Crossref Full Text | Google Scholar

47. Antioxidant status and biotechnological potential of new vischeria vischeri (eustigmatophyceae) soil strains in enrichment cultures.

PubMed Abstract | Google Scholar

48. Yang Y, Sun S, Xu W, Zhang Y, Yang R, Ma K, et al. Piperlongumine inhibits thioredoxin reductase 1 by targeting selenocysteine residues and sensitizes cancer cells to erastin. Antioxidants. (2022) 11:710.

PubMed Abstract | Google Scholar

49. The glutathione system: a journey from cyanobacteria to higher eukaryotes.

PubMed Abstract | Google Scholar

50. de Baat A, Meier DT, Rachid L, Fontana A, Böni-Schnetzler M, and Donath MY. Cystine/glutamate antiporter system xc- deficiency impairs insulin secretion in mice. Diabetologia. (2023) 66:2062–74.

PubMed Abstract | Google Scholar

51. Ozgur R, Uzilday B, Iwata Y, Koizumi N, and Turkan I. Interplay between the unfolded protein response and reactive oxygen species: A dynamic duo. J Exp Bot. (2018) 69:3333–45. doi: 10.1093/jxb/ery040

PubMed Abstract | Crossref Full Text | Google Scholar

52. Jurkowska H, Wróbel M, Jasek-Gajda E, and Rydz L. Sulfurtransferases and cystathionine beta-synthase expression in different human leukemia cell lines. Biomolecules. (2022) 12:148.

PubMed Abstract | Google Scholar

53. Kang YP, Mockabee-Macias A, Jiang C, Falzone A, Prieto-Farigua N, Stone E, et al. Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab. (2021) 33:174–89. doi: 10.1016/j.cmet.2020.12.007

PubMed Abstract | Crossref Full Text | Google Scholar

54. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. (2014) 156:317–31. doi: 10.1016/j.cell.2013.12.010

PubMed Abstract | Crossref Full Text | Google Scholar

55. Borchert A, Kalms J, Roth SR, Rademacher M, Schmidt A, Holzhutter HG, et al. Crystal structure and functional characterization of selenocysteine-containing glutathione peroxidase 4 suggests an alternative mechanism of peroxide reduction. Biochim Biophys Acta (BBA) - Mol Cell Biol Lipids. (2018) 1863:1095–107.

PubMed Abstract | Google Scholar

56. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. (2018) 172:409–22.

PubMed Abstract | Google Scholar

57. The first ADC bearing the ferroptosis inducer RSL3 as a payload with conservation of the fragile electrophilic warhead. Eur J Medicinal Chem. (2022) 244:114863. doi: 10.1016/j.ejmech.2022.114863

PubMed Abstract | Crossref Full Text | Google Scholar

58. Kim JW, Min DW, Kim D, Kim J, Kim MJ, Lim H, et al. GPX4 overexpressed non-small cell lung cancer cells are sensitive to RSL3-induced ferroptosis. Sci Rep. (2023) 13:8872. doi: 10.1038/s41598-023-35978-9

PubMed Abstract | Crossref Full Text | Google Scholar

59. Cotto-Rios XM and Gavathiotis E. Unraveling cell death mysteries. Nat Chem Biol. (2016) 12:470–1. doi: 10.1038/nchembio.2110

PubMed Abstract | Crossref Full Text | Google Scholar

60. Dimastrogiovanni D, Anselmi M, Miele AE, Boumis G, Petersson L, Angelucci F, et al. Combining crystallography and molecular dynamics: the case of Schistosoma mansoni phospholipid glutathione peroxidase. Proteins. (2010) 78:259–70. doi: 10.1002/prot.22536

PubMed Abstract | Crossref Full Text | Google Scholar

61. Huang J, Zhao Y, Luo X, Luo Y, Ji J, Li J, et al. Dexmedetomidine inhibits ferroptosis and attenuates sepsis-induced acute kidney injury via activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway. Redox Rep. (2024) 29:2430929. doi: 10.1080/13510002.2024.2430929

PubMed Abstract | Crossref Full Text | Google Scholar

62. Cheng S, Wan X, Yang L, Qin Y, Chen S, Liu Y, et al. RGCC-mediated PLK1 activity drives breast cancer lung metastasis by phosphorylating AMPKα2 to activate oxidative phosphorylation and fatty acid oxidation. J Exp Clin Cancer Res. (2023) 42:342. doi: 10.1186/s13046-023-02928-2

PubMed Abstract | Crossref Full Text | Google Scholar

63. Cen S, Peng X, Deng J, Jin H, Deng Z, Lin X, et al. The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway. Oncol Res. (2023) 31:375–88. doi: 10.32604/or.2023.028256

PubMed Abstract | Crossref Full Text | Google Scholar

64. Sinha A, Saini KK, Chandramouli A, Tripathi K, Khan MA, Satrusal SR, et al. ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis. Proc Natl Acad Sci U S A. (2024) 121:e2408049121. doi: 10.1073/pnas.2408049121

PubMed Abstract | Crossref Full Text | Google Scholar

65. Cifuentes C, Horndler L, Grosso P, Oeste CL, Hortal AM, Castillo J, et al. The R-RAS2 GTPase is a signaling hub in triple-negative breast cancer cell metabolism and metastatic behavior. J Hematol Oncol. (2025) 18:41. doi: 10.1186/s13045-025-01693-3

PubMed Abstract | Crossref Full Text | Google Scholar

66. Chen Z, Zhang G, Ren X, Yao Z, Zhou Q, Ren X, et al. Cross-talk between myeloid and B cells shapes the distinct microenvironments of primary and secondary liver cancer. Cancer Res. (2023) 83:3544–61. doi: 10.1158/0008-5472.CAN-23-0193

PubMed Abstract | Crossref Full Text | Google Scholar

67. Wei Y, Lao XM, Xiao X, Wang XY, Wu ZJ, Zeng QH, et al. Plasma cell polarization to the immunoglobulin G phenotype in hepatocellular carcinomas involves epigenetic alterations and promotes hepatoma progression in mice. Gastroenterology. (2019) 156:1890–904. doi: 10.1053/j.gastro.2019.01.250

PubMed Abstract | Crossref Full Text | Google Scholar

68. Liao T, Xu X, Wang G, and Yan J. p53-mediated suppression of the SLC7 A11/GPX4 signaling pathway promotes trophoblast ferroptosis in preeclampsia. BMC Biol. (2025) 23:141. doi: 10.1186/s12915-025-02240-9

PubMed Abstract | Crossref Full Text | Google Scholar

69. Wang Q, Hou Z, Liu Y, Wei D, Kong Q, and Chen X. Mechanism of acupuncture on cerebral ischemia-reperfusion injury via p53/SLC7A11/GPX4 signaling pathway in rat models. Zhongguo Zhen Jiu. (2025) 45:1099–110.

PubMed Abstract | Google Scholar

70. Zhang W, Dai J, Hou G, Liu H, Zheng S, Wang X, et al. SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation. Mol Cell.. (2023) 83:4352–69. doi: 10.1016/j.molcel.2023.10.042

PubMed Abstract | Crossref Full Text | Google Scholar

71. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. (2019) 575:688–92.

PubMed Abstract | Google Scholar

72. Chen Z, Han F, Du Y, Shi H, and Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. (2023) 8:70. doi: 10.1038/s41392-023-01332-8

PubMed Abstract | Crossref Full Text | Google Scholar

73. Abou Khouzam R, Janji B, Thiery J, Zaarour RF, Chamseddine AN, Mayr H, et al. Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy. Semin Cancer Biol. (2023) 97:104–23. doi: 10.1016/j.semcancer.2023.11.008

PubMed Abstract | Crossref Full Text | Google Scholar

74. Nagle AM, Levine KM, Tasdemir N, Scott JA, Burlbaugh K, Kehm J, et al. Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/insR inhibitors. Clin Cancer Res. (2018) 24:5165–77. doi: 10.1158/1078-0432.CCR-18-0279

PubMed Abstract | Crossref Full Text | Google Scholar

75. Bullock E and Brunton VG. E-cadherin-mediated cell-cell adhesion and invasive lobular breast cancer. Adv Exp Med Biol. (2025) 1464:259–75.

PubMed Abstract | Google Scholar

76. Vaupel P and Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. (2007) 26:225–39. doi: 10.1007/s10555-007-9055-1

PubMed Abstract | Crossref Full Text | Google Scholar

77. Angiogenesis in cancer and other diseases. nature.

Google Scholar

78. Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Commun Biol.

PubMed Abstract | Google Scholar

79. HIF1α-regulated expression of the fatty acid binding protein family is important for hypoxic reactivation of kaposi’s sarcoma-associated herpesvirus. J Virol. doi: 10.1128/jvi.02063-20

PubMed Abstract | Crossref Full Text | Google Scholar

80. Tian P, Xu Z, Guo J, Zhao J, Chen W, Huang W, et al. Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis. Redox Biol. (2024) 70:103073. doi: 10.1016/j.redox.2024.103073

PubMed Abstract | Crossref Full Text | Google Scholar

81. Yang Z, Su W, Wei X, Qu S, Zhao D, Zhou J, et al. HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1. Cell Rep. (2023) 42. doi: 10.1016/j.celrep.2023.112945

PubMed Abstract | Crossref Full Text | Google Scholar

82. Su X, Xie Y, Zhang J, Li M, Zhang Q, Jin G, et al. HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis. Cell Death Dis. (2022) 13:861. doi: 10.1038/s41419-022-05304-8

PubMed Abstract | Crossref Full Text | Google Scholar

83. Sun D, Sun X, Shi J, Shi X, Sun J, Luo C, et al. Oxygen-boosted fluorinated prodrug hybrid nanoassemblies for bidirectional amplification of breast cancer ferroptosis. J Controlled Release. (2025) 377:619–31.

PubMed Abstract | Google Scholar

84. Governing epidermal homeostasis by coupling cell–cell adhesion to integrin and growth factor signaling, proliferation, and apoptosis. doi: 10.1073/pnas.1202120109

PubMed Abstract | Crossref Full Text | Google Scholar

85. Goel HL, Karner ER, Kumar A, Mukhopadhyay D, Goel S, and Mercurio AM. YAP/TAZ-mediated regulation of laminin 332 is enabled by β4 integrin repression of ZEB1 to promote ferroptosis resistance. J Biol Chem. (2024) 300. doi: 10.1016/j.jbc.2024.107202

PubMed Abstract | Crossref Full Text | Google Scholar

86. Minikes AM, Song Y, Feng Y, Yoon C, Yoon SS, and Jiang X. E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer. Oncogene. (2023) 42:848–57.

PubMed Abstract | Google Scholar

87. Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, and Kasahara T. Anti-apoptotic role of focal adhesion kinase (FAK): INDUCTION OF INHIBITOR-OF-APOPTOSIS PROTEINS AND APOPTOSIS SUPPRESSION BY THE OVEREXPRESSION OF FAK IN a HUMAN LEUKEMIC CELL LINE, HL-60. J Biol Chem. (2000) 275:16309–15. doi: 10.1074/jbc.275.21.16309

PubMed Abstract | Crossref Full Text | Google Scholar

88. Wang S, Zhu L, Li T, Lin X, Zheng Y, Xu D, et al. Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma. Cell Rep Med. (2024) 5:101415. doi: 10.1016/j.xcrm.2024.101415

PubMed Abstract | Crossref Full Text | Google Scholar

89. Hao X, Zheng Z, Liu H, Zhang Y, Kang J, Kong X, et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing. Redox Biol. (2022) 56:102463. doi: 10.1016/j.redox.2022.102463

PubMed Abstract | Crossref Full Text | Google Scholar

90. Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Available online at.

Google Scholar

91. Xia X, Fan X, Zhao M, and Zhu P. The relationship between ferroptosis and tumors: A novel landscape for therapeutic approach. Curr Gene Ther. (2019) 19:117–24. doi: 10.2174/1566523219666190628152137

PubMed Abstract | Crossref Full Text | Google Scholar

92. Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell. (2023) 186:2748–64.

PubMed Abstract | Google Scholar

93. Zhang W, Dai J, Hou G, Liu H, Zheng S, Wang X, et al. SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation. Mol Cell. (2023) 83:4352–69. doi: 10.1016/j.molcel.2023.10.042

PubMed Abstract | Crossref Full Text | Google Scholar

94. Du S, Shi H, Xiong L, Wang P, and Shi Y. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol (Lausanne). (2022) 13:1011669.

PubMed Abstract | Google Scholar

95. Xu X, Xu XD, Ma MQ, Liang Y, Cai YB, Zhu ZX, et al. The mechanisms of ferroptosis and its role in atherosclerosis. BioMed Pharmacother. (2024) 171:116112.

Google Scholar

96. Liu M, Wu K, and Wu Y. The emerging role of ferroptosis in female reproductive disorders. BioMed Pharmacother. (2023) 166:115415.

Google Scholar

97. Zhang W, Sun Y, Bai L, Zhi L, Yang Y, Zhao Q, et al. RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11. J Clin Invest. (2021) 131:e152067. doi: 10.1172/JCI152067

PubMed Abstract | Crossref Full Text | Google Scholar

98. Parker JL, Deme JC, Kolokouris D, Kuteyi G, Biggin PC, Lea SM, et al. Molecular basis for redox control by the human cystine/glutamate antiporter system xc–. Nat Commun. (2021) 12:7147. doi: 10.1038/s41467-021-27414-1

PubMed Abstract | Crossref Full Text | Google Scholar

99. Zhang W, Feng J, Ni Y, Li G, Wang Y, Cao Y, et al. The role of SLC7A11 in diabetic wound healing: Novel insights and new therapeutic strategies. Front Immunol. (2024) 15:1467531. doi: 10.3389/fimmu.2024.1467531

PubMed Abstract | Crossref Full Text | Google Scholar

100. Koppula P, Zhang Y, Zhuang L, and Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun. (2018) 38:1–13. doi: 10.1186/s40880-018-0288-x

PubMed Abstract | Crossref Full Text | Google Scholar

101. Koppula P, Zhuang L, and Gan B. Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy.. Protein Cell. (2020) 12:599. doi: 10.1007/s13238-020-00789-5

PubMed Abstract | Crossref Full Text | Google Scholar

102. Zhang C, Liu X, Jin S, Chen Y, and Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. (2022) 21:47. doi: 10.1186/s12943-022-01530-y

PubMed Abstract | Crossref Full Text | Google Scholar

103. Chen Y, Fan Z, Hu S, Lu C, Xiang Y, and Liao S. Ferroptosis: a new strategy for cancer therapy. Front Oncol. (2022) 12:830561. doi: 10.3389/fonc.2022.830561

PubMed Abstract | Crossref Full Text | Google Scholar

104. Sacks D, Baxter B, Campbell BCV, Carpenter JS, Cognard C, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke. (2018) 13:612–32.

Google Scholar

105. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. (2014) 3:e02523. doi: 10.7554/eLife.02523

PubMed Abstract | Crossref Full Text | Google Scholar

106. Koeberle SC, Kipp AP, Stuppner H, and Koeberle A. Ferroptosis-modulating small molecules for targeting drug-resistant cancer: challenges and opportunities in manipulating redox signaling. Med Res Rev. (2023) 43:614–82. doi: 10.1002/med.21933

PubMed Abstract | Crossref Full Text | Google Scholar

107. Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ. (2020) 27:662–75. doi: 10.1038/s41418-019-0380-z

PubMed Abstract | Crossref Full Text | Google Scholar

108. Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signaling. (2013) 18:522–55. doi: 10.1089/ars.2011.4391

PubMed Abstract | Crossref Full Text | Google Scholar

109. Santacroce G, Gentile A, Soriano S, Novelli A, Lenti MV, and Di Sabatino A. Glutathione: pharmacological aspects and implications for clinical use in non-alcoholic fatty liver disease. Front Med. (2023) 10:1124275. doi: 10.3389/fmed.2023.1124275

PubMed Abstract | Crossref Full Text | Google Scholar

110. Dong J, Qi F, Qie H, Du S, Li L, Zhang Y, et al. Oleic acid inhibits SDC4 and promotes ferroptosis in lung cancer through GPX4/ACSL4. Clin Respir J. (2024) 18:e70014. doi: 10.1111/crj.70014

PubMed Abstract | Crossref Full Text | Google Scholar

111. Gong D, Chen M, Wang Y, Shi J, and Hou Y. Role of ferroptosis on tumor progression and immunotherapy. Cell Death Discovery. (2022) 8:427.

PubMed Abstract | Google Scholar

112. Zhao G, Liang J, Shan G, Gu J, Xu F, Lu C, et al. KLF11 regulates lung adenocarcinoma ferroptosis and chemosensitivity by suppressing GPX4. Commun Biol. (2023) 6:570. doi: 10.1038/s42003-023-04959-z

PubMed Abstract | Crossref Full Text | Google Scholar

113. Zhang W, Sun Y, Bai L, Zhi L, Yang Y, Zhao Q, et al. RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11. J Clin Invest. (2021) 131:e152067. doi: 10.1172/JCI152067

PubMed Abstract | Crossref Full Text | Google Scholar

114. Yasui C, Kono Y, Ishiguro R, Yagyu T, Kyoichi K, Yamamoto M, et al. New treatment modalities for colorectal cancer through simultaneous suppression of FSP1 and GPX4. Anticancer Res. (2024) 44:4905–14. doi: 10.21873/anticanres.17316

PubMed Abstract | Crossref Full Text | Google Scholar

115. Lee J and Roh JL. Unleashing ferroptosis in human cancers: targeting ferroptosis suppressor protein 1 for overcoming therapy resistance. Antioxid (basel Switz). (2023) 12:1218.

PubMed Abstract | Google Scholar

116. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. (2019) 575:688–92.

PubMed Abstract | Google Scholar

117. Gong J, Liu Y, Wang W, He R, Xia Q, Chen L, et al. TRIM21-promoted FSP1 plasma membrane translocation confers ferroptosis resistance in human cancers. Adv Sci (weinh Baden-wurtt Ger). (2023) 10:e2302318. doi: 10.1002/advs.202302318

PubMed Abstract | Crossref Full Text | Google Scholar

118. Lv Y, Liang C, Sun Q, Zhu J, Xu H, Li X, et al. Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat Commun. (2023) 14:5933. doi: 10.1038/s41467-023-41626-7

PubMed Abstract | Crossref Full Text | Google Scholar

119. Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. (2022) 608:778–83.

PubMed Abstract | Google Scholar

120. Xiang S, Yan W, Ren X, Feng J, and Zu X. Role of ferroptosis and ferroptosis-related long non’coding RNA in breast cancer. Cell Mol Biol Lett. (2024) 29:40. doi: 10.1186/s11658-024-00560-2

PubMed Abstract | Crossref Full Text | Google Scholar

121. Yang JS, Morris AJ, Kamizaki K, Chen J, Stark J, Oldham WM, et al. ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1. Cell. (2025) 188:2569–85.

PubMed Abstract | Google Scholar

122. Nishizawa H, Yamanaka M, and Igarashi K. Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal. FEBS J. (2023) 290:1688–704. doi: 10.1111/febs.16382

PubMed Abstract | Crossref Full Text | Google Scholar

123. Yuan S, Xi S, Weng H, Guo MM, Zhang JH, Yu ZP, et al. YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer. Cell Death Differ. (2023) 30:2477–90. doi: 10.1038/s41418-023-01234-w

PubMed Abstract | Crossref Full Text | Google Scholar

124. Lv Y, Wu M, Wang Z, and Wang J. Ferroptosis: from regulation of lipid peroxidation to the treatment of diseases. Cell Biol Toxicol. (2023) 39:827–51. doi: 10.1007/s10565-022-09778-2

PubMed Abstract | Crossref Full Text | Google Scholar

125. Kim JW, Kim MJ, Han TH, Lee JY, Kim S, Kim H, et al. FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner. Cell Death Dis. (2023) 14:567. doi: 10.1038/s41419-023-06070-x

PubMed Abstract | Crossref Full Text | Google Scholar

126. Villalpando-Rodriguez GE, Blankstein AR, Konzelman C, and Gibson SB. Lysosomal destabilizing drug siramesine and the dual tyrosine kinase inhibitor lapatinib induce a synergistic ferroptosis through reduced heme oxygenase-1 (HO-1) levels. Oxid Med Cell Longevity. (2019) 2019:9561281. doi: 10.1155/2019/9561281

PubMed Abstract | Crossref Full Text | Google Scholar

127. Zhang C, Qiao P, Xiao C, Cao Z, Chen J, Fang H, et al. Exosomal miR-375-3p mediated lipid metabolism, ferritinophagy and CoQ-dependent pathway contributes to the ferroptosis of keratinocyte in SJS/TEN. Int J Biol Sci. (2025) 21:1275–93. doi: 10.7150/ijbs.98592

PubMed Abstract | Crossref Full Text | Google Scholar

128. Zheng J and Conrad M. Ferroptosis: When metabolism meets cell death. Physiol Rev. (2025) 105:651–706. doi: 10.1152/physrev.00031.2024

PubMed Abstract | Crossref Full Text | Google Scholar

129. Pei S, Wei Y, Li Z, Zhong H, Dong J, Yi Z, et al. GSTP1 is a negative regulator of MAVS in the antiviral signaling against SVCV infection. Fish Shellfish Immunol. (2024) 146:109426. doi: 10.1016/j.fsi.2024.109426

PubMed Abstract | Crossref Full Text | Google Scholar

130. Liu X, Tan N, Liao H, Pan G, Xu Q, Zhu R, et al. High GSTP1 inhibits cell proliferation by reducing akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma. Oncotarget. (2018) 9:8957–71.

PubMed Abstract | Google Scholar

131. Zhu Y, Chen Y, Wang Y, Zhu Y, Wang H, Zuo M, et al. Glutathione S-transferase-pi 1 protects cells from irradiation-induced death by inhibiting ferroptosis in pancreatic cancer. FASEB J: Off Publ Fed Am Soc Exp Biol. (2024) 38:e70033. doi: 10.1096/fj.202400373RR

PubMed Abstract | Crossref Full Text | Google Scholar

132. Dong X, Yang Y, Zhou Y, Bi X, Zhao N, Zhang Z, et al. Glutathione S-transferases P1 protects breast cancer cell from adriamycin-induced cell death through promoting autophagy. Cell Death Differ. (2019) 26:2086–99. doi: 10.1038/s41418-019-0276-y

PubMed Abstract | Crossref Full Text | Google Scholar

133. Chen M, Du D, Zheng W, Liao M, Zhang L, Liang G, et al. Small hepatitis delta antigen selectively binds to target mRNA in hepatic cells: A potential mechanism by which hepatitis D virus downregulates glutathione S-transferase P1 and induces liver injury and hepatocarcinogenesis. Biochem Cell Biol = Biochim Biol Cell. (2019) 97:130–9. doi: 10.1139/bcb-2017-0321

PubMed Abstract | Crossref Full Text | Google Scholar

134. Kang YP, Mockabee-Macias A, Jiang C, Falzone A, Prieto-Farigua N, Stone E, et al. Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab. (2021) 33:174–89. doi: 10.1016/j.cmet.2020.12.007

PubMed Abstract | Crossref Full Text | Google Scholar

135. Ma X, Dong X, Xu Y, Ma N, Wei M, Xie X, et al. Identification of AP-1 as a critical regulator of glutathione peroxidase 4 (GPX4) transcriptional suppression and acinar cell ferroptosis in acute pancreatitis. Antioxid (basel Switz). (2022) 12:100. doi: 10.3390/antiox12010100

PubMed Abstract | Crossref Full Text | Google Scholar

136. Youssef E, Zhao S, Purcell C, Olson GL, and El-Deiry WS. Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy. Front Oncol. (2024) 14:1484515. doi: 10.3389/fonc.2024.1484515

PubMed Abstract | Crossref Full Text | Google Scholar

137. Bernatik O, Paclikova P, Sri Ganji R, and Bryja V. Activity of Smurf2 ubiquitin ligase is regulated by the wnt pathway protein dishevelled. Cells. (2020) 9:1147.

PubMed Abstract | Google Scholar

138. Wang Y, Liu Y, Liu J, Kang R, and Tang D. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun. (2020) 531:581–7. doi: 10.1016/j.bbrc.2020.07.032

PubMed Abstract | Crossref Full Text | Google Scholar

139. Zhang W, Dai J, Hou G, Liu H, Zheng S, Wang X, et al. SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation. Mol Cell. (2023) 83:4352–69. doi: 10.1016/j.molcel.2023.10.042

PubMed Abstract | Crossref Full Text | Google Scholar

140. Moroishi T, Hayashi T, Pan WW, Fujita Y, Holt MV, Qin J, et al. The hippo pathway kinases LATS1/2 suppress cancer immunity. Cell. (2016) 167:1525–39.

PubMed Abstract | Google Scholar

141. Belavgeni A, Tonnus W, and Linkermann A. Cancer cells evade ferroptosis: sex hormone-driven membrane-bound O-acyltransferase domain-containing 1 and 2 (MBOAT1/2) expression. Signal Transduct Target Ther. (2023) 8:336. doi: 10.1038/s41392-023-01593-3

PubMed Abstract | Crossref Full Text | Google Scholar

142. Liu Y, Lu S, Wu LL, Yang L, Yang L, and Wang J. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. (2023) 14:519. doi: 10.1038/s41419-023-06045-y

PubMed Abstract | Crossref Full Text | Google Scholar

143. Xie Y, Zhang S, Wu Y, Qi Y, Qi S, Chen X, et al. Pan-cancer analysis predicts MBOAT2 as a potential new ferroptosis related gene immune checkpoint. Discov Oncol. (2025) 16:322. doi: 10.1007/s12672-025-02078-1

PubMed Abstract | Crossref Full Text | Google Scholar

144. Liu Y and Chen M. Emerging role of α-klotho in energy metabolism and cardiometabolic diseases. Diabetes Metab Syndr. (2023) 17:102854. doi: 10.1016/j.dsx.2023.102854

PubMed Abstract | Crossref Full Text | Google Scholar

145. Jacenik D, Beswick EJ, Krajewska WM, and Prossnitz ER. G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis. World J Gastroenterol. (2019) 25:4092–104. doi: 10.3748/wjg.v25.i30.4092

PubMed Abstract | Crossref Full Text | Google Scholar

146. Jacenik D, Zielińska M, Mokrowiecka A, Michlewska S, Małecka-Panas E, Kordek R, et al. G protein-coupled estrogen receptor mediates anti-inflammatory action in crohn’s disease. Sci Rep. (2019) 9:6749. doi: 10.1038/s41598-019-43233-3

PubMed Abstract | Crossref Full Text | Google Scholar

147. Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG, and Gao LC. System Xc -/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. (2022) 13:910292. doi: 10.3389/fphar.2022.910292

PubMed Abstract | Crossref Full Text | Google Scholar

148. Yu FF, Zuo J, Wang M, Yu SY, Luo KT, Sha TT, et al. Selenomethionine alleviates T-2 toxin-induced articular chondrocyte ferroptosis via the system Xc-/GSH/GPX4 axis. Ecotoxicol Environ Saf. (2025) 290:117569.

PubMed Abstract | Google Scholar

149. Stewart A and Blakely RD. The ins and outs of dopamine transporter gene manipulation: in vivo models of DAT dysfunction. Adv Neurobiol. (2025) 46:235–70.

PubMed Abstract | Google Scholar

150. Zhang Y, Men J, Yin K, Zhang Y, Yang J, Li X, et al. Activation of gut metabolite ACSL4/LPCAT3 by microplastics in drinking water mediates ferroptosis via gut-kidney axis. Commun Biol. (2025) 8:211. doi: 10.1038/s42003-025-07641-8

PubMed Abstract | Crossref Full Text | Google Scholar

151. Gong C, Fu X, Ma Q, He M, Zhu X, Liu L, et al. Gastrodin: Modulating the xCT/GPX4 and ACSL4/LPCAT3 pathways to inhibit ferroptosis after ischemic stroke. Phytomedicine : Int J phytotherapy phytopharmacology. (2025) 136.

PubMed Abstract | Google Scholar

152. Müller F, Lim JKM, Bebber CM, Seidel E, Tishina S, Dahlhaus A, et al. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ. (2023) 30:442–56. doi: 10.1038/s41418-022-01096-8

PubMed Abstract | Crossref Full Text | Google Scholar

153. Huang W, Guo Y, Qian Y, Liu X, Li G, Wang J, et al. Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells. Eur J Med Chem. (2024) 276:116670. doi: 10.1016/j.ejmech.2024.116670

PubMed Abstract | Crossref Full Text | Google Scholar

154. Ajoolabady A, Tang D, Kroemer G, and Ren J. Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy. Br J Cancer. (2023) 128:190–205.

PubMed Abstract | Google Scholar

155. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. (2016) 63:173–84.

PubMed Abstract | Google Scholar

156. Wang L, Tong L, Xiong Z, Chen Y, Zhang P, Gao Y, et al. Ferroptosis-inducing nanomedicine and targeted short peptide for synergistic treatment of hepatocellular carcinoma. J Nanobiotechnology. (2024) 22:533.

PubMed Abstract | Google Scholar

157. Yu D, Hu H, Zhang Q, Wang C, Xu M, Xu H, et al. Acevaltrate as a novel ferroptosis inducer with dual targets of PCBP1/2 and GPX4 in colorectal cancer. Signal Transduct Target Ther. (2025) 10:211. doi: 10.1038/s41392-025-02296-7

PubMed Abstract | Crossref Full Text | Google Scholar

158. Conche C, Finkelmeier F, Pešić M, Nicolas AM, Böttger TW, Kennel KB, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. (2023) 72:1774–82.

PubMed Abstract | Google Scholar

159. Liu Y, Liu X, Wang H, Ding P, and Wang C. Agrimonolide inhibits cancer progression and induces ferroptosis and apoptosis by targeting SCD1 in ovarian cancer cells. Phytomedicine. (2022) 101:154102.

PubMed Abstract | Google Scholar

160. Deng M, Tang F, Chang X, Zhang Y, Liu P, Ji X, et al. A targetable OSGIN1 - AMPK - SLC2A3 axis controls the vulnerability of ovarian cancer to ferroptosis. NPJ Precis Oncol. (2025) 9:15. doi: 10.1038/s41698-024-00791-8

PubMed Abstract | Crossref Full Text | Google Scholar

161. Lyu Z, Wang H, Dai F, Lin Y, Wen H, Liu X, et al. Increased ZNF83 is a potential prognostic biomarker and regulates oxidative stress-induced ferroptosis in clear cell renal cell carcinoma. J Mol Med (Berl). (2025) 103:583–97. doi: 10.1007/s00109-025-02543-y

PubMed Abstract | Crossref Full Text | Google Scholar

162. More S, Bonnereau J, Wouters D, Spotbeen X, Karras P, Rizzollo F, et al. Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis. Sci Adv. (2024) 10:eadp6164. doi: 10.1126/sciadv.adp6164

PubMed Abstract | Crossref Full Text | Google Scholar

163. Freitas-Cortez MA, Masrorpour F, Jiang H, Mahmud I, Lu Y, Huang A, et al. Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins. Mol Cancer. (2025) 24:40.

PubMed Abstract | Google Scholar

164. Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P, et al. Loss of cardiac ferritin H facilitates cardiomyopathy via slc7a11-mediated ferroptosis. Circ Res. (2020) 127:486–501. doi: 10.1161/CIRCRESAHA.120.316509

PubMed Abstract | Crossref Full Text | Google Scholar

165. Identification and validation of ferroptosis-related gene signature in intervertebral disc degeneration.

Google Scholar

166. Huang G, He L, Liang B, Gao M, Huang J, Xia H, et al. Targeting PRMT1-mediated methylation of TAF15 to protect against myocardial infarction by inhibiting ferroptosis via the GPX4/NRF2 pathway. Clin Epigenetics. (2025) 17:129.

PubMed Abstract | Google Scholar

167. Zou P, Lin R, Fang Z, Chen J, Guan H, Yin J, et al. Implanted, wireless, self-powered photodynamic therapeutic tablet synergizes with ferroptosis inducer for effective cancer treatment. Advanced Science. (2023) 10:2302731.

PubMed Abstract | Google Scholar

168. Sun S, Shen J, Jiang J, Wang F, and Min J. Targeting ferroptosis opens new avenues for the development of novel therapeutics. Signal Transduct Target Ther. (2023) 8:372. doi: 10.1038/s41392-023-01606-1

PubMed Abstract | Crossref Full Text | Google Scholar

169. Metabolism of selenium, selenocysteine, and selenoproteins in ferroptosis in solid tumor cancers.

Google Scholar

170. Zhang W, Liu Y, Liao Y, Zhu C, and Zou Z. GPX4, ferroptosis, and diseases. Biomedicine pharmacotherapy = Biomedecine pharmacotherapie. (2024). doi: 10.1016/j.biopha.2024.116512

PubMed Abstract | Crossref Full Text | Google Scholar

171. Zhou L, Lian G, Zhou T, Cai Z, Yang S, Li W, et al. Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity. Nat Cancer. (2025) 6. doi: 10.1038/s43018-025-00937-y

PubMed Abstract | Crossref Full Text | Google Scholar

172. Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM, et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol. (2019) 26:623–33. doi: 10.1016/j.chembiol.2019.01.008

PubMed Abstract | Crossref Full Text | Google Scholar

173. Malumbres M. CDK4/6 inhibitors resTORe therapeutic sensitivity in HER2 + breast cancer. Cancer Cell. (2016) 29:243–4. doi: 10.1016/j.ccell.2016.02.016

PubMed Abstract | Crossref Full Text | Google Scholar

174. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. (2022) 185:2401–21. doi: 10.1016/j.cell.2022.06.003

PubMed Abstract | Crossref Full Text | Google Scholar

175. Hassannia B, Vandenabeele P, and Berghe TV. Targeting ferroptosis to iron out cancer. Cancer Cell. (2019) 35:830–49. doi: 10.1016/j.ccell.2019.04.002

PubMed Abstract | Crossref Full Text | Google Scholar

176. Namgaladze D, Fuhrmann DC, and Brüne B. Interplay of Nrf2 and BACH1 in inducing ferroportin expression and enhancing resistance of human macrophages towards ferroptosis. Cell Death Discovery. (2022) 8:327.

PubMed Abstract | Google Scholar

177. Fernández B, Olmedo P, Gil F, Fdez E, Naaldijk Y, Rivero-Ríos P, et al. Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB. Cell Death Dis. (2022) 13:1047. doi: 10.1038/s41419-022-05504-2

PubMed Abstract | Crossref Full Text | Google Scholar

178. Su H, Peng C, and Liu Y. Regulation of ferroptosis by PI3K/akt signaling pathway: A promising therapeutic axis in cancer. Front Cell Dev Biol. (2024) 12:1372330/full. doi: 10.3389/fcell.2024.1372330/full

Crossref Full Text | Google Scholar

179. Zhang HL, Hu BX, Ye ZP, Li ZL, Liu S, Zhong WQ, et al. TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer. Sci Transl Med. (2024) 16:eadk0330. doi: 10.1126/scitranslmed.adk0330

PubMed Abstract | Crossref Full Text | Google Scholar

180. Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, and Rouault TA. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. (2009) 9:461–73. doi: 10.1016/j.cmet.2009.03.006

PubMed Abstract | Crossref Full Text | Google Scholar

181. Chen GQ, Benthani FA, Wu J, Liang D, Bian ZX, and Jiang X. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ. (2020) 27:242–54. doi: 10.1038/s41418-019-0352-3

PubMed Abstract | Crossref Full Text | Google Scholar

182. Jiang X, Stockwell BR, and Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. (2021) 22:266–82. doi: 10.1038/s41580-020-00324-8

PubMed Abstract | Crossref Full Text | Google Scholar

183. Gardner HW. Oxygen radical chemistry of polyunsaturated fatty acids. Free Radical Biol Med. (1989) 7:65–86. doi: 10.1016/0891-5849(89)90102-0

PubMed Abstract | Crossref Full Text | Google Scholar

184. Grube J, Woitok MM, Mohs A, Erschfeld S, Lynen C, Trautwein C, et al. ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression. Cell Death Dis. (2022) 13:704. doi: 10.1038/s41419-022-05137-5

PubMed Abstract | Crossref Full Text | Google Scholar

185. Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP, et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol. (2022) 24. doi: 10.1038/s41556-021-00818-3

PubMed Abstract | Crossref Full Text | Google Scholar

186. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol. (1988) 35:95–125. doi: 10.1016/s0079-6603(08)60611-x

PubMed Abstract | Crossref Full Text | Google Scholar

187. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. (2007) 39:44–84. doi: 10.1016/j.biocel.2006.07.001

PubMed Abstract | Crossref Full Text | Google Scholar

188. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death differentiation.

PubMed Abstract | Google Scholar

189. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. (2022) 40:365–78. doi: 10.1016/j.ccell.2022.02.003

PubMed Abstract | Crossref Full Text | Google Scholar

190. Koppula P, Zhuang L, and Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. (2021) 12:599–620. doi: 10.1007/s13238-020-00789-5

PubMed Abstract | Crossref Full Text | Google Scholar

191. Kong R, Wang N, Han W, Bao W, and Lu J. IFNγ-mediated repression of system xc– drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells. J Leukocyte Biol. (2021) 110:301–14. doi: 10.1002/JLB.3MA1220-815RRR

PubMed Abstract | Crossref Full Text | Google Scholar

192. Yang M, Shen Z, Zhang X, Song Z, Zhang Y, Lin Z, et al. Ferroptosis of macrophages facilitates bone loss in apical periodontitis via NRF2/FSP1/ROS pathway. Free Radic Biol Med. (2023) 208:334–47. doi: 10.1016/j.freeradbiomed.2023.08.020

PubMed Abstract | Crossref Full Text | Google Scholar

193. Li G, Liao C, Chen J, Wang Z, Zhu S, Lai J, et al. Targeting the MCP-GPX4/HMGB1 axis for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma. Adv Sci (Weinh). (2024) 11:e2308208. doi: 10.1002/advs.202308208

PubMed Abstract | Crossref Full Text | Google Scholar

194. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. (2019) 18:10.

PubMed Abstract | Google Scholar

195. Liu L, Chen J, Bae J, Li H, Sun Z, Moore C, et al. Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells. Nat BioMed Eng. (2021) 5:1261–73.

PubMed Abstract | Google Scholar

196. Qiu Y, Wang X, Sun Y, Jin T, Tang R, Zhou X, et al. ACSL4-mediated membrane phospholipid remodeling induces integrin β1 activation to facilitate triple-negative breast cancer metastasis. Cancer Res. (2024) 84:1856–71. doi: 10.1158/0008-5472.CAN-23-2491

PubMed Abstract | Crossref Full Text | Google Scholar

197. Zhao X, Zhao Z, Li B, Huan S, Li Z, Xie J, et al. ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma. Cell Death Dis. (2024) 15:695. doi: 10.1038/s41419-024-07098-3

PubMed Abstract | Crossref Full Text | Google Scholar

198. Gan L, Lin X, Zhong Z, Zheng Y, Chen X, Chen J, et al. Ferroptosis meets cancer immunotherapy: Overcoming the crosstalk challenges through advanced drug delivery strategies. Acta Pharm Sin B. (2025). doi: 10.1016/j.apsb.2025.09.043

PubMed Abstract | Crossref Full Text | Google Scholar

199. Yang WS and Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. (2008) 15:234–45. doi: 10.1016/j.chembiol.2008.02.010

PubMed Abstract | Crossref Full Text | Google Scholar

200. Liang J, Bi G, Huang Y, Zhao G, Sui Q, Zhang H, et al. MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma. Drug Resist Updat. (2024) 73:101057. doi: 10.1016/j.drup.2024.101057

PubMed Abstract | Crossref Full Text | Google Scholar

201. Jiao Y, Cao F, and Liu H. Radiation-induced cell death and its mechanisms. Health Phys. (2022) 123:376–86. doi: 10.1097/HP.0000000000001601

PubMed Abstract | Crossref Full Text | Google Scholar

202. He J, Zhang Y, Luo S, Zhao Z, Mo T, Guan H, et al. Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis. Drug Resist Updat. (2025) 81:101250.

PubMed Abstract | Google Scholar

203. Niu X, Wang M, Wang M, Liu X, Zhang Y, Zheng P, et al. Dracorhodin perochlorate sensitizes colorectal cancer to ferroptosis by activating HMOX1 and inhibiting the SLC7A11/GPX4 axis. Int Immunopharmacol. (2025) 158:114827.

PubMed Abstract | Google Scholar

204. Hsieh MS, Ling HH, Setiawan SA, Hardianti MS, Fong IH, Yeh CT, et al. Therapeutic targeting of thioredoxin reductase 1 causes ferroptosis while potentiating anti-PD-1 efficacy in head and neck cancer. Chem Biol Interact. (2024) 395:111004. doi: 10.1016/j.cbi.2024.111004

PubMed Abstract | Crossref Full Text | Google Scholar

205. Sahu U, Mullarkey MP, Murphy SA, Anderson JC, Putluri V, Kamal AHM, et al. IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity. Nat Commun. (2025) 16:3874. doi: 10.1038/s41467-025-58911-2

PubMed Abstract | Crossref Full Text | Google Scholar

206. Cui Y, Zhang Z, Zhou X, Zhao Z, Zhao R, Xu X, et al. Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflammation. (2021) 18:249.

PubMed Abstract | Google Scholar

207. Cheff DM, Huang C, Scholzen KC, Gencheva R, Ronzetti MH, Cheng Q, et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. (2023) 62:102703. doi: 10.1016/j.redox.2023.102703

PubMed Abstract | Crossref Full Text | Google Scholar

208. Hendricks JM, Doubravsky CE, Wehri E, Li Z, Roberts MA, Deol KK, et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem Biol. (2023) 30:1090–103. doi: 10.1016/j.chembiol.2023.04.007

PubMed Abstract | Crossref Full Text | Google Scholar

209. Ji J, Cheng Z, Zhang J, Wu J, Xu X, Guo C, et al. Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway. J Cell Mol Med. (2024) 28:e18335. doi: 10.1111/jcmm.18335

PubMed Abstract | Crossref Full Text | Google Scholar

210. Koppula P, Zhuang L, and Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. (2021) 12. doi: 10.1007/s13238-020-00789-5

PubMed Abstract | Crossref Full Text | Google Scholar

211. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. (2021) 593:586–90.

Google Scholar

212. Feng Y, He Y, Zu R, Gong W, Gao Y, Wang Y, et al. 5-HT regulates resistance to aumolertinib by attenuating ferroptosis in lung adenocarcinoma. EMBO Mol Med. (2025) 17. doi: 10.1038/s44321-025-00293-5

PubMed Abstract | Crossref Full Text | Google Scholar

213. Zhao Z, He J, Qiu S, Wang L, Huangfu S, Hu Y, et al. Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis. Nat Commun. (2025) 16. doi: 10.1038/s41467-025-58992-z

PubMed Abstract | Crossref Full Text | Google Scholar

214. Zhou H, Qin D, Xie C, Zhou J, Jia S, Zhou Z, et al. Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia. Clin Cancer Res. (2024) 30:5430–44. doi: 10.1158/1078-0432.CCR-24-0796

PubMed Abstract | Crossref Full Text | Google Scholar

215. Jenke R, Oliinyk D, Zenz T, Körfer J, Schäker-Hübner L, Hansen FK, et al. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer. Biochem Pharmacol. (2024) 225. doi: 10.1016/j.bcp.2024.116257

PubMed Abstract | Crossref Full Text | Google Scholar

216. Proneth B and Conrad M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. (2019) 26:14–24. doi: 10.1038/s41418-018-0173-9

PubMed Abstract | Crossref Full Text | Google Scholar

217. Zhang F, Yan Y, Cai Y, Liang Q, Liu Y, Peng B, et al. Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications. Front Cell Dev Biol. (2023) 11. doi: 10.3389/fcell.2023.1112751

PubMed Abstract | Crossref Full Text | Google Scholar

218. Ma C, Hu H, Liu H, Zhong C, Wu B, Lv C, et al. Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy. Cell Biol Toxicol. (2025) 41. doi: 10.1007/s10565-025-10025-7

PubMed Abstract | Crossref Full Text | Google Scholar

219. Huang J, Zhao Y, Luo X, Luo Y, Ji J, Li J, et al. Dexmedetomidine inhibits ferroptosis and attenuates sepsis-induced acute kidney injury via activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway. Redox Rep. (2024) 29:2430929. doi: 10.1080/13510002.2024.2430929

PubMed Abstract | Crossref Full Text | Google Scholar

220. Rodencal J, Kim N, He A, Li VL, Lange M, He J, et al. Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest. Cell Chem Biol. (2024) 31:234–48. doi: 10.1016/j.chembiol.2023.10.011

PubMed Abstract | Crossref Full Text | Google Scholar

221. Kuang F, Liu J, Tang D, and Kang R. Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol. (2020) 8:586578. doi: 10.3389/fcell.2020.586578

PubMed Abstract | Crossref Full Text | Google Scholar

222. Liu J, Kang R, and Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. (2022) 289:7038–50. doi: 10.1111/febs.16059

PubMed Abstract | Crossref Full Text | Google Scholar

223. Su Y, Zhang B, Sun R, Liu W, Zhu Q, Zhang X, et al. PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application. Drug Deliv. (2021) 28:1397–418. doi: 10.1080/10717544.2021.1938756

PubMed Abstract | Crossref Full Text | Google Scholar

224. Rocha CV, Gonçalves V, da Silva MC, Bañobre-López M, and Gallo J. PLGA-based composites for various biomedical applications. Int J Mol Sci. (2022) 23:2034. doi: 10.3390/ijms23042034

PubMed Abstract | Crossref Full Text | Google Scholar

225. Ma Z, Sun Y, Yu Y, Xiao W, Xiao Z, Zhong T, et al. Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis. Cell Commun Signal. (2024) 22:295. doi: 10.1186/s12964-024-01669-9

PubMed Abstract | Crossref Full Text | Google Scholar

226. Scaranti M, Cojocaru E, Banerjee S, and Banerji U. Exploiting the folate receptor α in oncology. Nat Rev Clin Oncol. (2020) 17:349–59. doi: 10.1038/s41571-020-0339-5

PubMed Abstract | Crossref Full Text | Google Scholar

227. Cui J, Chen Y, Yang Q, Zhao P, Yang M, Wang X, et al. Protosappanin A protects DOX-induced myocardial injury and cardiac dysfunction by targeting ACSL4/FTH1 axis-dependent ferroptosis. Adv Sci (Weinh). (2024) 11:e2310227.

PubMed Abstract | Google Scholar

228. Wei X, Song M, Jin G, Jia W, Wang J, Liang M, et al. Multidimensional profiling of functionalized photothermal nanoplatforms for synergistic cancer immunotherapy: Design, strategy, and challenge. Coordination Chem Rev. (2024) 499:215488. doi: 10.1016/j.ccr.2023.215488

Crossref Full Text | Google Scholar

229. Chen G, Ma B, Wang Y, Xie R, Li C, Dou K, et al. CuS-based theranostic micelles for NIR-controlled combination chemotherapy and photothermal therapy and photoacoustic imaging. ACS Appl Mater Interfaces. (2017) 9:41700–11.

PubMed Abstract | Google Scholar

230. Qiang S, Hu X, Li R, Wu W, Fang K, Li H, et al. CuS nanoparticles-loaded and cisplatin prodrug conjugated fe(III)-MOFs for MRI-guided combination of chemotherapy and NIR-II photothermal therapy. ACS Appl Mater Interfaces. (2022) 14:36503–14.

PubMed Abstract | Google Scholar

231. Hu S, Zhang P, Cheng Q, Zhang L, Wu W, Sun J, et al. Codelivery of cuS and DOX into deep tumors with size and charge-switchable PAMAM dendrimers for chemo-photothermal therapy. ACS Appl Mater Interfaces. (2023) 15:53273–82.

PubMed Abstract | Google Scholar

232. Yan Y, Hu J, Han N, Li HT, Yang X, Li LG, et al. Sorafenib-loaded metal-organic framework nanoparticles for anti-hepatocellular carcinoma effects through synergistically potentiating ferroptosis and remodeling tumor immune microenvironment. Mater Today Bio. (2025) 32:101848. doi: 10.1016/j.mtbio.2025.101848

PubMed Abstract | Crossref Full Text | Google Scholar

233. Monaco ME. ACSL4: biomarker, mediator and target in quadruple negative breast cancer. Oncotarget. (2023) 14:563–75. doi: 10.18632/oncotarget.28453

PubMed Abstract | Crossref Full Text | Google Scholar

234. Li H, Sun Y, Yao Y, Ke S, Zhang N, Xiong W, et al. USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy. Proc Natl Acad Sci U S A. (2024) 121:e2315541121. doi: 10.1073/pnas.2315541121

PubMed Abstract | Crossref Full Text | Google Scholar

235. Candelaria PV, Leoh LS, Penichet ML, and Daniels-Wells TR. Antibodies targeting the transferrin receptor 1 (TfR1) as direct anti-cancer agents. Front Immunol. (2021) 12:607692. doi: 10.3389/fimmu.2021.607692

PubMed Abstract | Crossref Full Text | Google Scholar

236. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. (2021) 33:1001–12. doi: 10.1016/j.cmet.2021.02.015

PubMed Abstract | Crossref Full Text | Google Scholar

237. Ping Y, Shan J, Qin H, Li F, Qu J, Guo R, et al. PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis. Immunity. (2024) 57:2122–39.

PubMed Abstract | Google Scholar

238. Tao Q, Liu N, Wu J, Chen J, Chen X, and Peng C. Mefloquine enhances the efficacy of anti-PD-1 immunotherapy via IFN-γ-STAT1-IRF1-LPCAT3-induced ferroptosis in tumors. J Immunother Cancer. (2024) 12:e008554. doi: 10.1136/jitc-2023-008554

PubMed Abstract | Crossref Full Text | Google Scholar

239. Wang G, Wang JJ, Zhi-Min Z, Xu XN, Shi F, and Fu XL. Targeting critical pathways in ferroptosis and enhancing antitumor therapy of Platinum drugs for colorectal cancer. Sci Prog. (2023) 106. doi: 10.1177/00368504221147173

PubMed Abstract | Crossref Full Text | Google Scholar

240. Yang H, Zhang X, Jia Z, Wang H, Wu J, Wei X, et al. Targeting ferroptosis in prostate cancer management: molecular mechanisms, multidisciplinary strategies and translational perspectives. J Transl Med. (2025) 23:166. doi: 10.1186/s12967-025-06180-4

PubMed Abstract | Crossref Full Text | Google Scholar

241. Lv Y, Tang W, Xu Y, Chang W, Zhang Z, Lin Q, et al. Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis. Int J Biol Sci. (2023) 19:1284–98. doi: 10.7150/ijbs.74985

PubMed Abstract | Crossref Full Text | Google Scholar

242. Zhou X, Zou L, Liao H, Luo J, Yang T, Wu J, et al. Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer. Acta Pharm Sin B. (2022) 12:692–707. doi: 10.1016/j.apsb.2021.07.016

PubMed Abstract | Crossref Full Text | Google Scholar

243. Wang CK, Chen TJ, Tan GYT, Chang FP, Sridharan S, Yu CHA, et al. MEX3A mediates p53 degradation to suppress ferroptosis and facilitate ovarian cancer tumorigenesis. Cancer Res. (2023) 83:251–63. doi: 10.1158/0008-5472.CAN-22-1159

PubMed Abstract | Crossref Full Text | Google Scholar

244. S X, J H, W Z, C W, X L, Z K, et al. SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways. Oncogene. (2024) 43.

PubMed Abstract | Google Scholar

245. Tao B, Du R, Zhang X, Jia B, Gao Y, Zhao Y, et al. Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy. J Control Release. (2023) 363:692–706.

PubMed Abstract | Google Scholar

246. Wang J, Cao M, Han L, Shangguan P, Liu Y, Zhong Y, et al. Blood-brain barrier-penetrative fluorescent anticancer agents triggering paraptosis and ferroptosis for glioblastoma therapy. J Am Chem Soc. (2024) 146:28783–94. doi: 10.1021/jacs.4c07785

PubMed Abstract | Crossref Full Text | Google Scholar

247. Cui J, Chen Y, Yang Q, Zhao P, Yang M, Wang X, et al. Protosappanin A protects DOX-induced myocardial injury and cardiac dysfunction by targeting ACSL4/FTH1 axis-dependent ferroptosis. Adv Sci (Weinh). (2024) 11:e2310227.

PubMed Abstract | Google Scholar

248. Wang Z, Shen N, Wang Z, Yu L, Yang S, Wang Y, et al. TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11/xCT K11-linked ubiquitination and degradation. Cell Death Differ. (2024) 31:53–64. doi: 10.1038/s41418-023-01239-5

PubMed Abstract | Crossref Full Text | Google Scholar

249. Nagpal S, Milano MT, Chiang VL, Soltys SG, Brackett A, Halasz LM, et al. Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer. Neuro Oncol. (2024) 26:1195–212. doi: 10.1093/neuonc/noae041

PubMed Abstract | Crossref Full Text | Google Scholar

250. Sun L, Wang H, Yu S, Zhang L, Jiang J, and Zhou Q. Herceptin induces ferroptosis and mitochondrial dysfunction in H9c2 cells. Int J Mol Med. (2022) 49:17.

PubMed Abstract | Google Scholar

251. Saini KK, Chaturvedi P, Sinha A, Singh MP, Khan MA, Verma A, et al. Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc^–) in colorectal cancer. Redox Biol. (2023) :65:102833. doi: 10.1016/j.redox.2023.102833

PubMed Abstract | Crossref Full Text | Google Scholar

252. Cheng W, Kang K, Zhao A, and Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol. (2024) 17:54. doi: 10.1186/s13045-024-01581-2

PubMed Abstract | Crossref Full Text | Google Scholar

253. Hu S, Zhang P, Cheng Q, Zhang L, Wu W, Sun J, et al. Codelivery of cuS and DOX into deep tumors with size and charge-switchable PAMAM dendrimers for chemo-photothermal therapy. ACS Appl Mater Interfaces. (2023) 15:53273–82.

PubMed Abstract | Google Scholar

254. Li B, Chen X, Qiu W, Zhao R, Duan J, Zhang S, et al. Synchronous disintegration of ferroptosis defense axis via engineered exosome-conjugated magnetic nanoparticles for glioblastoma therapy. Adv Sci (Weinh). (2022) 9:e2105451. doi: 10.1002/advs.202105451

PubMed Abstract | Crossref Full Text | Google Scholar

255. Zhou H, Liu Z, Zhang Z, Pandey NK, Amador E, Nguyen W, et al. Copper-cysteamine nanoparticle-mediated microwave dynamic therapy improves cancer treatment with induction of ferroptosis. Bioact Mater. (2023) 24:322–30. doi: 10.1016/j.bioactmat.2022.12.023

PubMed Abstract | Crossref Full Text | Google Scholar

256. Yuan Y, Deng Y, Jin Y, Guo Z, Pan Y, Wang C, et al. Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRASG12C inhibitor-naïve Chinese patients with KRASG12C-mutated metastatic colorectal cancer: a pooled analysis from phase I part of two studies. Signal Transduct Target Ther. (2025) 10:241. doi: 10.1038/s41392-025-02315-7

PubMed Abstract | Crossref Full Text | Google Scholar

257. Zhou Q, Meng X, Sun L, Huang D, Yang N, Yu Y, et al. Efficacy and safety of KRASG12C inhibitor IBI351 monotherapy in patients with advanced NSCLC: results from a phase 2 pivotal study. J Thorac Oncol. (2024) 19:1630–9. doi: 10.1016/j.jtho.2024.08.005

PubMed Abstract | Crossref Full Text | Google Scholar

258. Wang M, Zhang Z, Li Q, Liu R, Li J, and Wang X. Multifunctional nanoplatform with near-infrared triggered nitric-oxide release for enhanced tumor ferroptosis. J Nanobiotechnology. (2024) 22:656.

PubMed Abstract | Google Scholar

259. Tian Y, He X, Yuan Y, Zhang S, Wang C, Dong J, et al. TME-responsive nanoplatform with glutathione depletion for enhanced tumor-specific mild photothermal/gene/ferroptosis synergistic therapy. Int J Nanomedicine. (2024) 19:9145–60.

PubMed Abstract | Google Scholar

260. Bala A. Biochemical ferrous ions (Fe2+) mediated fenton reaction: A biological prodigy for curing and developing autoimmune rheumatoid arthritis and cancer. J Environ Pathol Toxicol Oncol. (2025) 44:11–5. doi: 10.1615/JEnvironPatholToxicolOncol.2024053436

PubMed Abstract | Crossref Full Text | Google Scholar

261. Wu Z, Zhang L, Mao X, Zhu J, Li J, Wang C, et al. Ferrous iron metabolism modulator for immune stress regulation and its application in skin allograft models. J Am Chem Soc. (2025) 147:25325–36. doi: 10.1021/jacs.5c04246

PubMed Abstract | Crossref Full Text | Google Scholar

262. Wang X, Liu K, Gong H, Li D, Chu W, Zhao D, et al. Death by histone deacetylase inhibitor quisinostat in tongue squamous cell carcinoma via apoptosis, pyroptosis, and ferroptosis. Toxicol Appl Pharmacol. (2021) 410:115363. doi: 10.1016/j.taap.2020.115363

PubMed Abstract | Crossref Full Text | Google Scholar

263. Zhong L, Zhou S, Tong R, Shi J, Bai L, Zhu Y, et al. Preclinical assessment of histone deacetylase inhibitor quisinostat as a therapeutic agent against esophageal squamous cell carcinoma. Invest New Drugs. (2019) 37:616–24. doi: 10.1007/s10637-018-0651-4

PubMed Abstract | Crossref Full Text | Google Scholar

264. Li H, Yu K, Hu H, Zhang X, Zeng S, Li J, et al. METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer. Redox Biol. (2024) 71:103087. doi: 10.1016/j.redox.2024.103087

PubMed Abstract | Crossref Full Text | Google Scholar

265. Liu J, Lu X, Zeng S, Fu R, Wang X, Luo L, et al. ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer. Redox Biol. (2024) 71:103118. doi: 10.1016/j.redox.2024.103118

PubMed Abstract | Crossref Full Text | Google Scholar

266. Fernández-Acosta R, Vintea I, Koeken I, Hassannia B, and Vanden Berghe T. Harnessing ferroptosis for precision oncology: challenges and prospects. BMC Biol. (2025) 23. doi: 10.1186/s12915-025-02154-6

PubMed Abstract | Crossref Full Text | Google Scholar

267. Chen X, Kang R, Kroemer G, and Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. (2021) 18:280–96. doi: 10.1038/s41571-020-00462-0

PubMed Abstract | Crossref Full Text | Google Scholar

268. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. (2019) 12. doi: 10.1186/s13045-019-0720-y

PubMed Abstract | Crossref Full Text | Google Scholar

269. Liu Y, Yu Z, Lu Y, Liu Y, Chen L, and Li J. Progress in the study of the mechanism of ferroptosis in coronary heart disease and clinical intervention strategies. Front Cardiovasc Med. (2025) 12:1545231/full. doi: 10.3389/fcvm.2025.1545231/full

PubMed Abstract | Crossref Full Text | Google Scholar

270. Sun K, Shi Y, Yan C, Wang S, Han L, Li F, et al. Glycolysis-derived lactate induces ACSL4 expression and lactylation to activate ferroptosis during intervertebral disc degeneration. Adv Sci (Weinh). (2025) 12:e2416149. doi: 10.1002/advs.202416149

PubMed Abstract | Crossref Full Text | Google Scholar

271. Ursini F and Maiorino M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med. (2020) 152:175–85. doi: 10.1016/j.freeradbiomed.2020.02.027

PubMed Abstract | Crossref Full Text | Google Scholar

272. Alborzinia H, Ignashkova TI, Dejure FR, Gendarme M, Theobald J, Wölfl S, et al. Golgi stress mediates redox imbalance and ferroptosis in human cells. Commun Biol. (2018) 1:210. doi: 10.1038/s42003-018-0212-6

PubMed Abstract | Crossref Full Text | Google Scholar

273. Schwab A, Rao Z, Zhang J, Gollowitzer A, Siebenkäs K, Bindel N, et al. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat Cell Biol. (2024) 26:1470–81. doi: 10.1038/s41556-024-01464-1

PubMed Abstract | Crossref Full Text | Google Scholar

274. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition. Nat Cell Biol.

PubMed Abstract | Google Scholar

275. Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes. Cell Death Dis.

PubMed Abstract | Google Scholar

276. Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell Death differentiation.

PubMed Abstract | Google Scholar

277. Adedoyin O, Boddu R, Traylor A, Lever JM, Bolisetty S, George JF, et al. Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells. Am J Physiol Renal Physiol. (2018) 314:F702–14. doi: 10.1152/ajprenal.00044.2017

PubMed Abstract | Crossref Full Text | Google Scholar

278. Battaglia AM, Sacco A, Perrotta ID, Faniello MC, Scalise M, Torella D, et al. Iron administration overcomes resistance to erastin-mediated ferroptosis in ovarian cancer cells. Front Oncol. (2022) 12:868351/full. doi: 10.3389/fonc.2022.868351/full

PubMed Abstract | Crossref Full Text | Google Scholar

279. Shen X, Obore N, Wang Y, Yu T, and Yu H. The role of ferroptosis in placental-related diseases. Reprod Sci. (2023) 30:2079–86. doi: 10.1007/s43032-023-01193-0

PubMed Abstract | Crossref Full Text | Google Scholar

280. Luo S, Zeng Y, Chen B, Yan J, Ma F, Zhuang G, et al. Vitamin E and GPX4 cooperatively protect treg cells from ferroptosis and alleviate intestinal inflammatory damage in necrotizing enterocolitis. Redox Biol. (2024) :75:103303. doi: 10.1016/j.redox.2024.103303

PubMed Abstract | Crossref Full Text | Google Scholar

281. Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. (2022) 15:174. doi: 10.1186/s13045-022-01392-3

PubMed Abstract | Crossref Full Text | Google Scholar

282. Cui Y, Zhang Z, Zhou X, Zhao Z, Zhao R, Xu X, et al. Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. J Neuroinflammation. (2021) 18:249.

PubMed Abstract | Google Scholar

283. Chen X, Tsvetkov AS, Shen HM, Isidoro C, Ktistakis NT, Linkermann A, et al. International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis. Autophagy. (2024) 20:1213–46. doi: 10.1080/15548627.2024.2319901

PubMed Abstract | Crossref Full Text | Google Scholar

284. Radaelli E, Assenmacher CA, Verrelle J, Banerjee E, Manero F, Khiati S, et al. Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis. eLife. (2023) 12:e84710. doi: 10.7554/eLife.84710

PubMed Abstract | Crossref Full Text | Google Scholar

285. Yu H, Guo P, Xie X, Wang Y, and Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Medi. (2017) 21:648–57.

Google Scholar

286. Kang R, Kroemer G, and Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. (2019) 133:162–8. doi: 10.1016/j.freeradbiomed.2018.05.074

PubMed Abstract | Crossref Full Text | Google Scholar

287. Zhou C, Yu T, Zhu R, Lu J, Ouyang X, Zhang Z, et al. Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation. Int J Biol Sci. (2023) 19:1471–89. doi: 10.7150/ijbs.77979

PubMed Abstract | Crossref Full Text | Google Scholar

288. Huang G, Cai Y, Ren M, Zhang X, Fu Y, Cheng R, et al. Salidroside sensitizes Triple-negative breast cancer to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy. J Adv Res. (2025) 74:589–607. doi: 10.1016/j.jare.2024.09.027

PubMed Abstract | Crossref Full Text | Google Scholar

289. Qi R, Bai Y, Li K, Liu N, Xu Y, Dal E, et al. Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs. Drug Resist Updat. (2023) 68:100960. doi: 10.1016/j.drup.2023.100960

PubMed Abstract | Crossref Full Text | Google Scholar

290. Huang Y, Xu W, and Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol. (2021) 18:2114–27. doi: 10.1038/s41423-021-00740-6

PubMed Abstract | Crossref Full Text | Google Scholar

291. Zheng H, Liu J, Cheng Q, Zhang Q, Zhang Y, Jiang L, et al. Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance. Nat Cancer. (2024) 5:572–89.

PubMed Abstract | Google Scholar

292. Stratton MR, Campbell PJ, and Futreal PA. The cancer genome. Nature. (2009) 458:719–24.

Google Scholar

293. Negrini S, Gorgoulis VG, and Halazonetis TD. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol. (2010) 11:220–8. doi: 10.1038/nrm2858

PubMed Abstract | Crossref Full Text | Google Scholar

294. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. (2001) 293:876–80.

Google Scholar

295. Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ Breast cancer by expanding the cancer stem cell population. Mol Cell. (2012) 47:570–84. doi: 10.1016/j.molcel.2012.06.014

PubMed Abstract | Crossref Full Text | Google Scholar

296. Shiao SL, Ganesan AP, Rugo HS, and Coussens LM. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. (2011) 25:2559–72. doi: 10.1101/gad.169029.111

PubMed Abstract | Crossref Full Text | Google Scholar

297. Yang C, He L, He P, Liu Y, Wang W, He Y, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol. (2015) 32:14. doi: 10.1007/s12032-014-0352-6

PubMed Abstract | Crossref Full Text | Google Scholar

298. Gilbert LA and Hemann MT. DNA damage-mediated induction of a chemoresistant niche. Cell. (2010) 143:355–66.

PubMed Abstract | Google Scholar

299. Tian Y, Lei Y, Wang Y, Lai J, Wang J, and Xia F. Mechanism of multidrug resistance to chemotherapy mediated by P−glycoprotein (Review). Int J Oncol. (2023) 63:119. doi: 10.3892/ijo.2023.5567

PubMed Abstract | Crossref Full Text | Google Scholar

300. Shan G, Gu J, Zhou D, Li L, Cheng W, Wang Y, et al. Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Exp Mol Med. (2020) 52:1809–22. doi: 10.1038/s12276-020-0431-z

PubMed Abstract | Crossref Full Text | Google Scholar

301. Guan Z, Jin X, Guan Z, Liu S, Tao K, and Luo L. The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF-1α to inhibit knee osteoarthritis-induced ferroptosis. Aging Cell. (2023) 22:e13807. doi: 10.1111/acel.13807

PubMed Abstract | Crossref Full Text | Google Scholar

302. Haoyue W, Kexiang S, Shan TW, Jiamin G, Luyun Y, Junkai W, et al. Icariin promoted ferroptosis by activating mitochondrial dysfunction to inhibit colorectal cancer and synergistically enhanced the efficacy of PD-1 inhibitors. Phytomedicine. (2025) 136:156224. doi: 10.1016/j.phymed.2024.156224

PubMed Abstract | Crossref Full Text | Google Scholar

303. Zhang Q, Deng T, Zhang H, Zuo D, Zhu Q, Bai M, et al. Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemoresistance in colorectal cancer. Adv Sci (Weinh). (2022) 9:e2203357. doi: 10.1002/advs.202203357

PubMed Abstract | Crossref Full Text | Google Scholar

304. Wang Y, Liu Z, Li L, Zhang Z, Zhang K, Chu M, et al. Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke. J Nanobiotechnology. (2024) 22:291.

PubMed Abstract | Google Scholar

305. Song L, Yuan X, Zhao Z, Wang P, Wu W, and Wang J. A biomimetic nanocarrier strategy targets ferroptosis and efferocytosis during myocardial infarction. Int J Nanomedicine. (2024) 19:8253–70.

PubMed Abstract | Google Scholar

306. Papadopoulos C. Molecular and immunometabolic landscape of erythrophagocytosis-induced ferroptosis. Cardiovasc Hematol Disord Drug Targets. (2025) 25:79–86.

PubMed Abstract | Google Scholar

307. Jiang Z, Lim SO, Yan M, Hsu JL, Yao J, Wei Y, et al. TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J Clin Invest. (2021) 131:e139434. doi: 10.1172/JCI139434

PubMed Abstract | Crossref Full Text | Google Scholar

308. Wang S, Zhu L, Li T, Lin X, Zheng Y, Xu D, et al. Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma. Cell Rep Med. (2024) 5:101415. doi: 10.1016/j.xcrm.2024.101415

PubMed Abstract | Crossref Full Text | Google Scholar

309. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. (2022) 40:365–78. doi: 10.1016/j.ccell.2022.02.003

PubMed Abstract | Crossref Full Text | Google Scholar

310. Yu Y, Huang X, Liang C, and Zhang P. Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer. Eur J Pharmacol. (2023) 957:176007. doi: 10.1016/j.ejphar.2023.176007

PubMed Abstract | Crossref Full Text | Google Scholar

311. Mansoori B, Mohammadi A, Davudian S, Shirjang S, and Baradaran B. The different mechanisms of cancer drug resistance: A brief review. Adv Pharm Bull. (2017) 7:339–48. doi: 10.15171/apb.2017.041

PubMed Abstract | Crossref Full Text | Google Scholar

312. Lei Z, Tian Q, Teng Q, Wurpel JND, Zeng L, Pan Y, et al. Understanding and targeting resistance mechanisms in cancer. MedComm. (2023) 4:e265. doi: 10.1002/mco2.265

PubMed Abstract | Crossref Full Text | Google Scholar

313. Baguley BC. Multiple drug resistance mechanisms in cancer. Mol Biotechnol. (2010) 46:308–16. doi: 10.1007/s12033-010-9321-2

PubMed Abstract | Crossref Full Text | Google Scholar

314. Zhu J, Huang L, Yang J, Li Z, Wu L, Xiong W, et al. A CIA strategy with eminent drug-loading capacities for tumor ferroptosis-gas synergistic therapy. Theranostics. (2024) 14:7349–69.

PubMed Abstract | Google Scholar

315. Xu SY, Yin SS, Wang L, Zhong H, Wang H, and Yu HY. Insights into emerging mechanisms of ferroptosis: new regulators for cancer therapeutics. Cell Biol Toxicol. (2025) 41:63. doi: 10.1007/s10565-025-10010-0

PubMed Abstract | Crossref Full Text | Google Scholar

316. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. (2017) 171:273–85. doi: 10.1016/j.cell.2017.09.021

PubMed Abstract | Crossref Full Text | Google Scholar

317. Pan G, Xia Y, Hao M, Guan J, Zhu Q, Zha T, et al. EZH2 suppresses IR-induced ferroptosis by forming a co-repressor complex with HIF-1α to inhibit ACSL4: Targeting EZH2 enhances radiosensitivity in KDM6A-deficient esophageal squamous carcinoma. Cell Death Differ. (2025) 32:1026–40. doi: 10.1038/s41418-025-01451-5

PubMed Abstract | Crossref Full Text | Google Scholar

318. Lu J, Xu F, and Lu H. LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci. (2020) 260:118305. doi: 10.1016/j.lfs.2020.118305

PubMed Abstract | Crossref Full Text | Google Scholar

319. Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5. Cell Death Discov. (2025). Available online at: https://www.nature.com/articles/s41420-020-00306-x.

PubMed Abstract | Google Scholar

320. CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes. Nat Chem Biol. (2025). Available online at: https://www.nature.com/articles/s41589-023-01512-1.

PubMed Abstract | Google Scholar

321. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. (2017) 13:91–8. doi: 10.1038/nchembio.2239

PubMed Abstract | Crossref Full Text | Google Scholar

322. Chen Y, Li L, Lan J, Cui Y, Rao X, Zhao J, et al. CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma. Mol Cancer. (2022) 21:11.

PubMed Abstract | Google Scholar

323. Yue H, Zhan Y, Zhang Z, Liang W, and Wu Z. The emerging role of ferroptosis in myocardial fibrosis of atrial fibrillation. Arch Med Sci. (2023) 19:507–12. doi: 10.5114/aoms/160941

PubMed Abstract | Crossref Full Text | Google Scholar