Abstract
Programmed cell death (PCD) is equally important for maintaining overall homeostasis as it is for cell proliferation. The dynamic balance between cell proliferation and PCD promotes the body’s continuous self-repair and self-renewal, thus achieving cellular homeostasis. However, when this balance is disrupted, such as through unrestricted cell proliferation or the inhibition of PCD, tumors may occur. Moreover, this inhibition of cell death is considered a major cause of tumor development and a key factor contributing to the poor efficacy of many tumor treatments. Nowadays, with the discovery of an increasing number of PCD modalities, such as necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis, PCD has broken the traditional classification of “apoptotic necrosis.” It is also an evolutionary necessity to prevent systemic damage caused by blocking a single cell death pathway. A systematic study of PCD may provide new insights into the origin of malignant tumors, the sensitivity of normal and malignant cells to treatment, and the development of treatment resistance. However, treatment regimens that act on PCD all pose significant cardiovascular risks, including excessive apoptosis of cardiomyocytes, cardiac rhythm abnormalities, cardiac remodeling, and myocarditis, among others. Currently, research on cardiovascular risks in tumor treatment is still incomplete. In this review, we describe different types of cell death processes and their roles in tumorigenesis. At the same time, we also discuss the basic and clinical applications of PCD in tumor pathogenesis, prevention, and treatment, as well as the known or potential cardiovascular risks. This provides a theoretical basis for the continuous progress of PCD-based tumor treatments.
Introduction
Inducing programmed cell death (PCD) appropriately represents a critical strategy in the development of anti-tumor drugs (Liu et al., 2022). Currently, cell death pathways are categorized into two major types: accidental cell death (ACD) and PCD (Radi, Stewart and O'Neil, 2018). ACD occurs following exposure to severe physical, chemical, or mechanical insults, with necrosis being its sole manifestation, observed in both infectious and noninfectious disease contexts (Peng et al., 2022). In contrast, PCD encompasses a diverse repertoire including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, cuproptosis, and other modalities (; ; Peng et al., 2022). As illustrated in Figure 1, PCD serves a pivotal role in maintaining homeostasis and regulating growth and development in multicellular organisms (; Wu et al., 2020). This process is fundamental to sustaining physiological balance, as both normal and tumor cells rely on PCD for self-renewal and growth regulation (). Importantly, research has linked impaired PCD to tumorigenesis, disease progression, and the development of drug resistance across multiple cancer. Consequently, the targeted induction and activation of PCD have emerged as a focal area in oncotherapy (Tong et al., 2022).
FIGURE 1
Notably, many anti-tumor agents including classical alkylating agents, targeted therapies, and immune checkpoint inhibitors-exert their effects through modulation of PCD pathways (Kciuk et al., 2024; Wang et al., 2024b; Wu et al., 2023; Xiao et al., 2021a). However, clinical applications of chemotherapeutics, targeted drugs, and immune checkpoint inhibitors have revealed significant cardiovascular risks (; ; Wang et al., 2024a). Alarmingly, these treatment-related cardiovascular complications lead cancer patients to die of cardiovascular disease rather than the primary malignancy. (Sayour et al., 2024). This highlights the necessity of incorporating cardiac function monitoring as a standard component of oncological care. This review systematically discusses the current understanding of PCD in tumor treatment, the clinical applications of related therapeutic agents, and their potential cardiovascular toxicities, aiming to provide a theoretical foundation for safeguarding cardiovascular health during cancer therapy.
Basic studies and clinical studies
Specific descriptions of PCD
Each of PCD is governed by distinct molecular regulatory networks and exhibits unique morphological and biochemical hallmarks (Yuan and Ofengeim, 2024), as summarized in Table 1. The evolution of multiple PCD represents an adaptive strategy for multicellular organisms. Throughout the lifecycle, innumerable “redundant” or “pathologically altered” cells must be eliminated (Kulkarni and Hardwick, 2023). Relying exclusively on a single death mechanism would pose critical risks: inhibition of such a pathway-whether due to genetic mutation, pathogen evasion, or therapeutic intervention-could disrupt cellular homeostasis, potentially leading to uncontrolled proliferation (as in cancer) or excessive inflammation. This functional redundancy in PCD therefore serves as a robust safeguard, ensuring that disruptions in one pathway can be compensated for by others, thereby maintaining organismal integrity across diverse physiological and pathological contexts (Tower, 2015).
TABLE 1
| Type of cell death | Key molecule | Morphological change |
|---|---|---|
| Necrosis | None | Cell swelling, membrane rupture, loss of organelle |
| Apoptosis | Bax, Bak, Caspase8, Caspase3, Caspase9 | Cell shrinkage, collapse of subcellular structure, condensation of chromatin, fragmentation of nucleus, formation of plasma membrane vesicles |
| Necroptosis | TNFα, caspase-8, RIPK1, RIPK3, MLKL | Membrane rupture, expansion of cytoplasm and organelles, chromosome condensation, release of cellular contents |
| Pyroptosis | NLRs, ALRs, Caspase1, Caspase11 | Cell swelling, membrane rupture, chromosome condensation and fragmentation |
| Autophagy | ULK1, ATGs, LC3, mTOR, Beclin1 | Membrane integrity, autophagosomes and vesicles formed |
| Ferroptosis | Fe2+, GPX4, GSH, MDA,ROS,LPO | Diminutive mitochondria, decreased cristae, collapsed and ruptured membrane |
| Cuproptosis | Cu2+, FDX1,DLAT, LIAS | Membrane integrity, collapse of subcellular structure |
Summary of multiple cell death pathways.
Abbreviations in the table: Bax, BCL2-associated X; bak, BCL2 antagonist/killer; TNFα, Tumor Necrosis Factor α; RIPK1/3, Receptor Interacting Protein Kinases 1/3; MLKL, Mixed Lineage Kinase Domain-Like Protein; NLRs, Nucleotide-binding Leucine-rich Repeat Receptors; ALRs, AIM2-Like Receptors; ULK1, Unc-51, Like Autophagy Activating Kinase 1; ATGs, Autophagy-Related Genes; LC3, Microtubule-Associated Protein 1 Light Chain 3; mTOR, mechanistic target of rapamycin; GPX4, Glutathione Peroxidase 4; GSH, glutathione; MDA, malondialdehyde; ROS, reactive oxygen species; LPO, lipid peroxidation; FDX1, Ferredoxin 1; DLAT, dihydrolipoamide acetyltransferase; LIAS, lipoyl synthase.
Apoptosis
Apoptosis is a caspase-dependent form of PCD that occurs under defined physiological or pathological conditions (Kesavardhana et al., 2020; Obeng, 2021). Apoptosis proceeds without cell membrane rupture, a critical difference from necrosis that minimizes collateral tissue damage (). Apoptosis is generally classified into two categories: the extrinsic apoptosis pathway and the intrinsic apoptosis pathway. The extrinsic apoptosis pathway, referred to in the text as the death receptor pathway, is triggered by the binding of extracellular death ligands to death receptors on the cell surface, which in turn activates a series of caspase proteases, leading to cell apoptosis (; ; ). B-cell lymphoma/leukemia-2 protein (BCL-2) protein is a core member of the BCL-2 family and plays a key regulatory role in apoptosis, especially in the intrinsic apoptosis pathway (Kaufman et al., 2021). The intrinsic apoptosis pathway is activated when cells are exposed to internal stress factors (such as DNA damage, oxidative stress, protein misfolding, etc.). This leads to changes in mitochondrial function and structure, alterations in mitochondrial membrane permeability, and the release of substances such as cytochrome c into the cytoplasm. This, in turn, activates caspase proteases, triggering apoptosis (Figure 2A) (Kesavardhana et al., 2020; Warren et al., 2019; Zhang et al., 2019).
FIGURE 2
When the heart is stimulated by chemotherapeutic drugs it results in the release of large amounts of reactive oxygen species (ROS) and activates oxidative stress in cardiomyocytes. Excessive oxidative stress damage the DNA, proteins and lipids of cardiomyocytes and activates the apoptotic signaling pathway of cardiomyocytes, leading to apoptosis of cardiomyocyte (; Peng et al., 2024). Cardiomyocytes are the main functional units of cardiac contraction and diastole, and massive apoptosis of cardiomyocytes leads to a decrease in cardiac contractility and a series of adverse effects, such as arrhythmia, ventricular remodeling, and ultimately, heart failure (HF) (Pan et al., 2024).
Pyroptosis
Pyroptosis is a pro-inflammatory form of PCD executed via canonical or noncanonical pathways, distinguished by the formation of plasma membrane pores and release of pro-inflammatory cytokines (Shi et al., 2017; Yu et al., 2021). The canonical pathway is initiated by pathogen-associated molecular patterns (PAMPs) or Damage-Associated Molecular Patterns (DAMPs) activating cytosolic pattern recognition receptors (PRRs), such as nucleotide-binding oligomerization domain-like receptors (NLRs). Upon ligand recognition, NLRs oligomerize with apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) to form inflammasomes, which recruit and activate pro-caspase-1 (; Shi et al., 2015). Activated caspase-1 then cleaves the gasdermin D (GSDMD) protein, releasing its N-terminal domain that translocates to the plasma membrane, forming pores that induce osmotic lysis (Zhou et al., 2020). Concurrently, caspase-1 processes pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their active forms, which are released through the pores to propagate inflammatory responses (Sarhan et al., 2018). The noncanonical pathway involves cytosolic detection of bacterial lipopolysaccharides (LPS) by caspase-4/5 (in humans) or caspase-11, leading to GSDMD activation and subsequent pore formation without inflammasome assembly, though it also results in IL-1β/IL-18 release and cell membrane rupture (). This tightly regulated process links microbial infection or cellular stress to controlled inflammation, highlighting pyroptosis as a critical interface between innate immunity and RCD (Figure 2B).
Beyond GSDMD, the Gasdermin family member GSDME has been recognized as an alternative executor of pyroptosis. Under physiological or pathological conditions, GSDME can be cleaved by caspase-3, caspase-8, or granzyme A, liberating its N-terminal domain to form membrane pores and induce pyroptotic cell death (Sarhan et al., 2018; Zhou et al., 2020). Consequently, a defining characteristic of pyroptosis is the proteolytic activation of Gasdermin proteins, whose N-terminal fragments oligomerize to form membrane-disrupting pores, ultimately leading to lytic cell death and the release of inflammatory mediators.
Programmed necrosis
Programmed cell death, necroptosis, when it used as a technical term, represents a caspase-independent modality of PCD that is activated when canonical apoptotic pathways are functionally inhibited (). Morphologically, this process is characterized by features of necrosis, including loss of plasma membrane integrity, cytoplasmic and organellar swelling, chromatin condensation, and release of intracellular components, such as DAMPs, proinflammatory cytokines, and chemokines-thereby instigating a robust inflammatory response in vivo (Figure 2C) (; ; Snyder and Oberst, 2021).
Necroptosis is executed through a tightly regulated signaling cascade involving receptor-interacting protein kinases 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Activation initiates when RIPK1 and RIPK3 assemble via their RIP homotypic interaction motifs (RHIMs), undergoing sequential autophosphorylation and trans-phosphorylation to form a functional necrosome complex. Phosphorylated RIPK3 then recruits and phosphorylates MLKL, triggering its oligomerization and translocation to the plasma membrane and intracellular organelle membranes. At these sites, phosphorylated MLKL forms pore-forming complexes in biological membranes, leading to membrane rupture, cytoplasmic content leakage into the extracellular space, and the characteristic inflammatory phenotype of necroptosis. Concurrently, this process releases DAMPs, DAMPs are endogenous molecular patterns released by damaged or dying cells during injury, activating immune cells like macrophages and triggering inflammatory responses, including interleukin-1α (IL-1α), IL-1β, and IL-33, which act as danger signals to recruit immune cells to sites of tissue injury, facilitating clearance of necroptotic cells and orchestrating local inflammatory responses (Martens et al., 2021; Zhao et al., 2012).
When Programmed Necrosis is used as a broad concept, it refers to a genetically regulated process of cell death characterized by features like necrosis. It encompasses various specific forms of cell death, including necroptosis, pyroptosis, and ferroptosis, among others, which will not be elaborated upon here. Mitochondrial-dependent necrosis is a specific form of necrosis that is typically closely associated with the opening of the mitochondrial permeability transition pore (mPTP). When the mPTP opens, it leads to mitochondrial dysfunction, such as the cessation of ATP synthesis driven by respiration and the collapse of the mitochondrial membrane potential, ultimately triggering cell necrosis. This represents an important pathway within Programmed Necrosis. ().
Autophagy
Autophagy enables cells to adapt to stress or injury by degrading cytoplasmic constituents (; ). Morphologically and mechanistically, autophagy is defined by the enzymatic degradation of proteins and organelles via lysosomal hydrolases, and the formation of double-membrane vesicles reflecting dynamic rearrangement of cellular membranes (Figure 3) ().
FIGURE 3
Autophagy patterns represent a range of conserved strategies for cellular quality control, nutrient cycling, and stress adaptation. While macroautophagy is usually associated with non-selective bulk degradation (although selective degradation via cargo receptors such as p62/SQSTM1 is possible), microautophagy and CMA show a higher degree of specificity, highlighting the functional diversity of autophagic processes in maintaining cellular homeostasis and coordinating PCD.
Ferroptosis
Dr. Brent R Stockwell first introduced the concept of “iron metamorphosis” in 2012 (). This is a unique mode of cell death characterized by iron-dependent lipid peroxidation and massive accumulation of ROS. The central mechanism of the iron metabolic response lies in the induction of cell death by lipid peroxidation of unsaturated fatty acids highly expressed on cell membranes catalyzed by the action of divalent iron or ester oxygenases (; Li and Li, 2020). In addition, the expression of antioxidant systems, namely glutathione (GSH) and glutathione peroxidase 4 (GPX4), is also inhibited (Figure 4A) (Li and Li, 2020).
FIGURE 4
In the cell membrane, phospholipids produce lipid ROS through non-enzymatic (Fenton reaction) or enzymatic (lipid oxidase) processes, while iron acts as a catalyst. These lipid ROS accumulate and undergo peroxidation with polyunsaturated fatty acids (PUFA) in the cell membrane. This ultimately leads to cell membrane rupture and cell death (Jiang et al., 2021; Li and Li, 2020).
Cuproptosis
Cuproptosis, the central mechanism is that excessive intracellular accumulation of copper (Cu2+)-through copper ion imports or dysregulated mitochondrial respiration-binds to the key enzyme in the pyruvate dehydrogenase complex, thioacylated dihydrolipoamide S-acetyltransferase (DLAT). This interaction induces DLAT oligomerization and aggregation, leading to the formation of insoluble protein clusters that disrupt mitochondrial metabolism and trigger cytotoxicity, ultimately leading to cell death (Figure 4B) (Tsvetkov et al., 2022).
Treatment regimens/targets and cardiovascular risks for different types of PCD
Cardiovascular risks for various PCD-targeting cancer treatment regimens
Apoptosis has long been recognized as an important mechanism to prevent tumorigenesis, and inhibition of apoptosis is one of the characteristics of tumor cells (). The molecular mechanisms that inhibit apoptosis in tumor cells include disrupting the balance between pro- and anti-apoptotic proteins (; ; Mohamad Anuar et al., 2020), inhibiting caspase activity (Jung et al., 2021; Sangaran et al., 2021), and disrupting death receptor signaling (; Xu et al., 2021). Caspases have been found to be key proteins in the initiation and execution of apoptosis, and their reduced expression or impaired function is closely associated with tumor progression (Kesavardhana et al., 2020). Loss of caspase 3 expression and function has been found to promote the survival of a variety of tumor cells ().
Chemotherapy
Chemotherapy is the longest and most widely used drugs in tumor treatment, such as cyclophosphamide, fluorouracil, adriamycin (DOX), and some plant bases. Chemotherapy is usually aimed at interfering with the growth and division of tumor cells, including interfering with the DNA synthesis and protein synthesis processes of tumor cells to achieve tumor suppression (Peng et al., 2024). Since chemotherapeutic agents act on rapidly growing and dividing cells, they inevitably harm cells that are metabolically active, causing side effects such as myelosuppression, alopecia, liver and kidney damage, and cardiomyocyte damage (). The process of chemotherapy is closely related to PCD. Currently, radiotherapy and chemotherapy attempt to induce apoptosis by activating the killing potential of caspase 3. However, new studies have shown that caspase 3 is not an oncogenic but a pro-oncogenic factor after cells are exposed to chemicals and radiation (Yosefzon et al., 2018). It has been shown that caspase 3 is involved in promoting tumor repopulation after radiotherapy through a paracrine signaling pathway (). In addition, caspase 3 promotes tumor growth by providing a pro-angiogenic microenvironment. Researchers have found that colon tumor patients with low caspase 3 activation have longer disease-free survival (Kunac et al., 2019).
Targeting drug
Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors, as classical tumor-targeting agents, are not described in detail here. The Bcl-2 family plays key regulatory roles by inhibiting apoptosis and promoting apoptosis. Bcl-2 and/or Bcl-XL are overexpressed in many human tumors such as gastrointestinal tumors, lymphomas, neuroblastomas, and bladder cancers. High expression of Bcl-2 inhibits apoptosis and accelerates cell growth, which in turn leads to malignancy (Song et al., 2021; Tao et al., 2021). The anti-apoptotic protein Bcl-2 has become an emerging drug target in cancer therapy (; Song et al., 2021). In the past 20 years, various inhibitors have been introduced, and some drugs have entered the clinical stage. Statistically, some Bcl-2 inhibitors have entered the clinical study stage, which are Oblimersen, Navitoclax (ABT-263), Venetoclax (ABT-199), and Obataclax mesylate (GX15-070), among which Venetoclax has been approved for marketing in 2016 (; Jiménez-Guerrero et al., 2018; Pullarkat et al., 2021; Walker et al., 2021; Wei et al., 2020). Impaired death receptor signaling pathway is also one of the mechanisms by which tumor cells evade apoptosis. Studies have shown that tumor cells acquire drug resistance by downregulating the expression of death receptors. For example, reduced expression of CD95 inhibits the apoptotic pathway, leading to resistance to chemotherapy in patients with leukemia or neuroblastoma (; ).
Immune checkpoint inhibitors (ICIs)
ICIs potentiate systemic immune responses, particularly T cell-mediated antitumor immunity, by abrogating tumor-induced immunosuppression and can also induce tumor cell apoptosis via extrinsic death receptor pathways (). Since the 2011 FDA approval of the CTLA-4 inhibitor ipilimumab, the first ICIs for melanoma numerous ICIs have entered clinical trials or achieved market launch, including the PD-1 inhibitor nivolumab and PD-L1 inhibitor atezolizumab. CTLA-4 is expressed on T cells and competes with the co-stimulatory molecule CD28 for binding to B7 molecules on antigen-presenting cells. This interaction inhibits T-cell activation. CTLA-4 inhibitors like ipilimumab block CTLA-4, enhancing T-cell activation and promoting an immune response against tumor cells. PD-1 also acts on T cells, PD-1 is expressed on the surface of activated T cells, PD-L1 is often overexpressed on tumor cells. When PD-1 binds to PD-L1, it sends an inhibitory signal to T cells, preventing them from attacking tumor cells. PD-1 inhibitors, such as pembrolizumab and nivolumab, block the interaction between PD-1 and PD-L1, enabling T cells to regain their anti-tumor activity (; Rittmeyer et al., 2017). Emerging ICIs in clinical development target additional pathways such as LAG-3, TIGIT, and TIM-3, expanding the therapeutic landscape of immune-oncology ().
Necroptosis in tumor treatment
A dual role in both promoting and reducing tumor growth has been identified in various cancer (Qin et al., 2019). Necroptosis serves as a fail-safe mechanism of cell death in cells where apoptosis cannot be induced, thereby inhibiting tumor progression. However, necroptosis, as a form of PCD, can trigger inflammatory responses, which have been reported to promote cancer metastasis and immunosuppression (Najafov et al., 2017).
The RIPK1/RIPK3 complex, a critical regulator of necroptosis, has been found to be downregulated in samples from cancer patients, including colorectal cancer (Stoll et al., 2017), gastric cancer (), acute myeloid leukemia (AML) (Nugues et al., 2014), and melanoma (). Additionally, RIPK1/RIPK3 has been implicated in colorectal cancer. In a cohort study involving over 100 patients, low RIPK3 expression was independently associated with reduced disease-free survival and overall survival (). Similarly, low RIPK3 expression predicts poor prognosis in gastric cancer (). These findings suggest that RIPK3 may exert anti-inflammatory and anti-tumor effects in cancer. However, in some animal models, RIPK1 inhibition has been linked to adverse cardiovascular effects, such as myocardial inflammation or structural cardiac alterations. Notably, excessive activation of the RIPK1 pathway may induce cardiac dysfunction (). As the executioner of necroptosis, MLKL, upon activation, induces plasma membrane rupture and initiates the necroptotic process. Current research indicates that MLKL-encoded mRNA can promote MLKL expression in the tumor microenvironment, leading to necroptosis in tumor cells.
Pyroptosis in cancer treatment
Extensive studies have demonstrated that pyroptosis is closely associated with the development and metastasis of various cancers. Prolonged exposure to an inflammatory environment increases the risk of cancer. Specifically, pyroptosis induces the release of cytokines such as IL-1 and IL-18, which can promote tumor invasion, thereby enhancing tumorigenesis and metastatic potential. Pyroptosis acts as a double-edged sword in cancer, capable of either promoting or suppressing tumorigenesis. While its pro-tumorigenic effects have been widely investigated, the relationship between pyroptosis and anti-cancer immunity remains incompletely understood (Yu et al., 2021).
In lung cancer, PPVI (a saponin derived from Trillium tschonoskii Maxim) inhibits the proliferation of NSCLC cells via the ROS/NF-κB/NLRP3/GSDMD signaling pathway, exhibiting significant anti-tumor effects. Given the low chemosensitivity of NSCLC, this mechanism suggests that PPVI may represent a novel therapeutic target for NSCLC in the future (Teng et al., 2020).
Currently, many chemotherapeutic agents exert anti-tumor effects by inducing pyroptosis. For instance, in triple-negative breast cancer, cisplatin (CDDP) appears to increase the complete pathological response rate and suppress tumor growth and metastasis in vitro and in vivo by activating the NLRP3/caspase-1/GSDMD-mediated pyroptosis pathway (Yan et al., 2021). Sorafenib, a kinase inhibitor, reduces MHC-I expression in HCC tumor cells. It has been reported to exert anti-tumor effects by inducing pyroptosis in macrophages. Beyond this indirect mechanism, pyroptosis also directly exhibits significant anti-tumor properties in HCC cells (; ). In recent years, CAR-T therapy has demonstrated remarkable efficacy in treating tumors, particularly B-cell acute lymphoblastic leukemia (B-ALL), with complete remission rates reaching 90%. CAR-T cells can induce pyroptosis in primary B-ALL cells by rapidly releasing granzyme B, activating caspase-3 to cleave GSDME, and ultimately triggering pyroptosis (Zhang et al., 2021).
Recent studies have validated pyroptosis as a feasible anti-tumor immune mechanism with clinical potential. Many researchers are exploring combinations of pyroptosis with other cancer therapies to modulate pyroptosis and inhibit tumor cell proliferation, migration, and invasion. Potential targeted strategies include inhibiting NLRP3, caspase-1, caspase-3, and GSDMD (Li et al., 2021).
Auxiliary role of autophagy in cancer treatment
Autophagy exerts a pronounced dual role in tumors, contributing to the limited development of autophagy-targeting antitumor drugs. Chloroquine (CQ) and hydroxychloroquine (HCQ) are among the few autophagy-targeting compounds that have entered clinical investigations (Levy et al., 2017). Their mechanism of action involves lysosomal deacidification, which prevents autophagosomes from fusing with lysosomes and achieving complete degradation of their cargo (Yang et al., 2013). The more detailed mechanism by which CQ induces lysosomal deacidification remains unclear. Preliminary clinical trials indicate that CQ or HCQ are well-tolerated, particularly without the neurodegenerative side effects observed in mice with knockout of certain autophagy-related (ATG) genes, which are associated with neurodegeneration (). As a major metabolite of CQ, HCQ exhibits lower toxicity at peak concentrations, leading to its increased use in clinical trials. While overall efficacy reports are positive, most trials enroll a small number of patients, necessitating further validation of results ().
Ferroptosis in cancer treatment
Researchers are increasingly recognizing that various conventional cancer therapies can induce ferroptosis, and enhancing ferroptosis induced by these treatments may further improve therapeutic efficacy. Radiotherapy (RT) triggers ferroptosis through multiple parallel mechanisms (Pearson et al., 2021). Following RT, tumor cells activate adaptive responses—such as upregulating SLC7A11 or GPX4 expression—to antagonize RT-induced ferroptosis. Thus, combining RT with FINs (ferroptosis inducers) targeting SLC7A11 or GPX4 increases sensitivity of tumor cells or xenograft tumors to radiation by enhancing ferroptotic susceptibility (Pearson et al., 2021). Similarly, the chemotherapeutic agent gemcitabine induces GPX4 expression and activity; GPX4 inhibition counteracts this effect, increasing gemcitabine sensitivity in tumor cells and xenografts via ferroptosis induction. The cardiovascular risks of gemcitabine are typically linked to factors such as dosage, treatment duration, and preexisting cardiovascular conditions, with reported symptoms including myocardial ischemia (e.g., chest pain, tightness), rarely progressing to myocardial infarction. Targeting SLC7A11 with FINs has also been shown to sensitize tumor cells to chemotherapy (e.g., CDDP, doxorubicin, DOX), immunotherapy (e.g., ICIs), and combined RT-immunotherapy (Lang et al., 2019).
Notably, in cancer with intrinsic or acquired treatment resistance, induction of ferroptosis by FINs restores sensitivity to conventional therapies. Mutations in tumor suppressors TP53 or KEAP1 evade RT-induced ferroptosis by upregulating SLC7A11 and other anti-ferroptotic mechanisms, leading to inherent radiation resistance (Zheng et al., 2022). Acquired radioresistant tumor cells also exhibit SLC7A11 upregulation and ferroptosis resistance; in these cells and xenografts, FINs reactivate ferroptotic sensitivity, restoring responsiveness to RT. Similarly, FINs can overcome chemoresistance in certain cancers: targeting SLC7A11 with FINs eliminates CDDP resistance in head and neck squamous cell carcinoma cells and xenografts (), while in vitro studies show FIN-mediated SLC7A11 inhibition reverses docetaxel resistance in ovarian tumor cells ().
Cuproptosis in cancer treatment
Cuproptosis is a newly discovered copper-dependent form of PCD identified in 2022. Currently, research on drugs for treating tumors caused by copper death is still in its early stages. Elesclomol (ES) is a chemotherapeutic adjuvant developed by synta pharmaceuticals and originally developed for treating metastatic melanoma. Recent studies have found that its synergistic effect with copper ions can specifically induce cuproptosis by degrading iron-sulfur proteins and interfering with mitochondrial metabolism. ES is primarily used in cancer therapy research, with its mechanisms involving cuproptosis, oxidative stress-induced cell death, and mitochondrial function regulation. There are currently no reported explicit applications in the cardiovascular field. Cuproptosis is often combined with other PCD mechanisms (such as apoptosis and ferroptosis) or traditional therapies to overcome the limitations of single mechanisms.
PCD-dependent oncology drugs and cardiovascular risks
Chemotherapeutic drugs are one of the most widely used and longest-established types of tumor treatment drugs (Zhou et al., 2023). Numerous existing studies have shown that anthracyclines (Hulst et al., 2022), taxanes (Sun et al., 2022), and alkylating agents (Kreher et al., 2023) all exhibit significant cardiotoxicity (Figures 5,6). Anthracyclines represented by DOX, or epirubicin and daunorubicin, induce DNA damage by intercalating into DNA and inhibiting topoisomerase II, thereby activating cell apoptosis pathways (van der Voort et al., 2021). While DOX acts on cancer cells, it also binds to cardiac myocyte-specific topoisomerase II, leading to double-strand breaks in myocardial nuclear DNA. The DNA damage is difficult to repair, triggering the p53-dependent apoptosis pathway (; Lin et al., 2022). Additionally, after entering cardiac myocytes, DOX intercalates into the mitochondrial membrane lipid bilayer and disrupts the mitochondrial electron transport chain, leading to electron leakage and subsequent production and release of reactive oxygen species (ROS) (Kim and Choi, 2021; Xie et al., 2022). ROS induces the expression of Bcl-2 associated X protein (Bax)/Bcl-2 homologous antagonist/killer protein (Bak), leading to increased mitochondrial membrane permeability. Subsequently, cytochrome C is released to activate Caspase-9, which in turn activates Caspase-3 to execute the apoptotic process of cardiac myocytes (; Shen et al., 2021).
FIGURE 5
FIGURE 6
Anthracyclines
Anthracyclines have been widely used in clinical cancer treatment. According to the timing of cardiac toxicity appearance, they can be classified into acute toxicity, subacute toxicity, and chronic toxicity (; ). Acute toxicity occurs within hours to days after drug administration, caused by transient myocardial cell dysfunction due to a massive burst of ROS in the short term (). Subacute myocardial toxicity occurs within weeks to months after drug administration. During this phase, persistent accumulation of ROS leads to severe DNA damage in myocardial cells, triggering myocardial cell apoptosis and partial myocardial necrosis (). Chronic toxicity occurs years after drug administration or even persists lifelong. In contrast to the former two, chronic toxicity involves severe myocardial cell loss and long-term cardiac fibrosis, leading to irreversible cardiac dysfunction such as dilated cardiomyopathy and New York Heart Association (NYHA) class III-IV HF (Figure 7) (Xie et al., 2024). In clinical use of anthracyclines, cardiac function changes must be monitored via echocardiography, B-type natriuretic peptide (BNP) levels, troponin levels, and electrocardiography. Interventions should be initiated when significant changes in indicators of HF risk occur, including angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), β-blockers, spironolactone, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors (Porter et al., 2022).
FIGURE 7
To reduce the cardiac damage caused by anthracycline chemotherapy, several clinical application protocols and preclinical studies have made multi-faceted efforts. On the one hand, it is about how to reduce the cardiotoxicity of anthracyclines under the premise of ensuring chemotherapeutic efficacy, and on the other hand, how to enhance the heart’s ability to cope with anthracyclines (). Clinical practice often involves replacing short-term high-dose administration of DOX with continuous infusion or fractional dosing to reduce its cardiotoxicity (Pollack et al., 2020). Preclinical studies aim to alter the in vivo distribution of drugs to reduce the cardiotoxicity of anthracyclines, including some newly developed drug delivery systems such as DOX liposomes and DOX nanoparticles (; Yang et al., 2024). Some cardioprotective drugs are commonly used to protect the heart from anthracycline-induced damage, typically by influencing the redox metabolic processes of cardiac myocytes. Take Dexrazoxane as an example: it chelates iron ions from the Fe3+-anthracycline complex, inhibits hydroxyl radical formation, and directly scavenges superoxide anions (; Huang et al., 2024). Reduced GSH is another commonly used reducing agent. In DOX-induced cardiotoxicity, GSH reduces DOX cardiac toxicity by enhancing superoxide dismutase (SOD) activity and decreasing the expression of Bax/Bcl-2 apoptotic signaling (Huang et al., 2024).
Taxanes
Taxanes, like anthracyclines, also lead to increased of ROS in cardiac myocytes, primarily superoxide anions (O2−) and hydrogen peroxide (H2O2). Generally, the cardiotoxicity of taxanes is much less severe than that of anthracyclines (Mosca et al., 2021; Xiao et al., 2021b). However, taxanes do affect the mitochondrial fusion-fission process (You et al., 2021). For example, docetaxel induces dynamin-related protein 1 (Drp1)-mediated abnormal mitochondrial fission, leading to collapse of the mitochondrial membrane potential (ΔΨm) and a 50% increase in cytochrome c release (Xiong et al., 2024). Taxanes also affect cellular structure by stabilizing microtubules and blocking mitosis to induce tumor cell apoptosis, while simultaneously interacting with cardiac tubulin to disrupt cytoskeletal integrity and trigger myocardial cell apoptosis (). All the above effects on cardiac myocytes can lead to myocardial cell loss and trigger cardiac dysfunction, manifested as reduced left ventricular ejection fraction and congestive HF (Lu et al., 2025).
Unlike anthracyclines, taxanes also affect the normal rhythm of the heart. Some studies have shown that paclitaxel can directly bind to the human ether-a-go-go related gene (hERG) channel (a potassium ion channel) in cardiac myocytes and prolong the action potential, leading to QT interval prolongation (Rathkopf et al., 2025). When paclitaxel acts on Ca2+-ATPase, it can cause intracellular Ca2+ overload in cardiac myocytes and lead to cardiac rhythm abnormalities, manifested as sinus bradycardia or supraventricular tachycardia (Wang et al., 2022). In addition, histamine release by taxanes can cause vasodilation and hypotension, leading to acute cardiovascular disorders or chronic cardiac injury (Tsao et al., 2022).
Alkylating agents
Alkylating agents are one of the earliest and most widely used anticancer drugs. Compared with anthracycline anticancer drugs, alkylating agents have a lower incidence of cardiotoxicity (). Clinically, alkylating agents associated with cardiotoxicity mainly include Cyclophosphamide (CTX) (), Ifosfamide (IFO) (), and platinum compounds such as CDDP (Oaknin et al., 2024) and Carboplatin (CBP) (). CTX exhibits a certain probability of causing hemorrhagic myocarditis, typically occurring with high-dose use (>100 mg/kg). CDDP can directly damage cardiomyocytes. Upon entering cardiomyocytes, it binds to DNA or proteins, disrupting normal cellular metabolism. Since CDDP affects ion channels such as calcium and potassium channels, its administration is often accompanied by alterations in cardiomyocyte action potentials and repolarization, potentially leading to arrhythmias (Panopoulos et al., 2023; Pudil et al., 2020). Given their early use and well-established clinical application, details will not be repeated here.
Targeted drugs
Targeted therapies, particularly HER2 inhibitors like trastuzumab and pertuzumab, exhibit notable cardiotoxic potential. These agents block HER2-mediated oncogenic signaling and enhance antibody-dependent cellular cytotoxicity but also disrupt HER2-dependent survival pathways in cardiomyocytes, impairing myocardial repair and promoting apoptosis (Kirkham et al., 2022).
For the known cardiotoxicity of HER2 inhibitors, clinical practice generally allows for the occurrence of cardiotoxicity with certain drugs. Take trastuzumab as an example: echocardiography and troponin level monitoring are typically used to assess cardiotoxicity risk and determine whether continued use of HER2-targeted inhibitors is appropriate. When left ventricular ejection fraction (LVEF) significantly decreases (50% < LVEF ≤ 90%) and cardiac troponin levels increase, interventions are initiated with ACEIs/ARBs and/or β-blockers, accompanied by increased frequency of echocardiographic monitoring (Porter et al., 2022).
Although BCL-2 inhibitors exhibit promising clinical activity in oncology, they pose cardiovascular risks by antagonizing the anti-apoptotic function of BCL-2 in cardiac myocytes, disrupting energy metabolism, and inducing ventricular remodeling. Additionally, BCL-2 inhibition alters cardiac electrophysiology by regulating potassium channels and delaying repolarization, thereby prolonging the QT interval—a known risk factor for life-threatening arrhythmias (; Zhang et al., 2016).
Immune checkpoint inhibitors
ICIs, while revolutionizing cancer treatment through immune activation, carry unique cardiovascular hazards. T cell-mediated immune attack on cardiomyocytes and systemic cytokine storms—characterized by acute surges in IL-6, IFN-γ, and other pro-inflammatory cytokines—can trigger myocarditis, cardiomyocyte apoptosis, and circulatory collapse with high mortality (Sun et al., 2024).
During clinical use of ICIs, electrocardiograms, troponin levels, echocardiograms, and follow-up with symptom change recording are required. Any abnormal test results necessitate further evaluation. In the presence of significant cardiotoxic symptoms such as myocarditis, pericarditis, arrhythmias, or ventricular dysfunction, prompt intervention with corticosteroid drugs is indicated. For cases refractory to initial steroids, consideration should be given to adding mycophenolate mofetil, infliximab, or antithymocyte globulin ().
Other related channels
In addition, some drugs that are still in the research phase or may pose potential cardiovascular risks through intrapathway analysis also warrant attention. MLKL is a key executioner protein in the necroptosis pathway. However, other studies suggest that excessive MLKL activation may trigger oxidative stress in cardiomyocytes, resulting in necrotic cell death. This also implies that inducing tumor cell necroptosis carries potential cardiotoxic risks (; Zhang et al., 2016). Pyroptosis exerts anti-tumor effects through inflammasome activation, eliciting robust immune responses. However, in cardiovascular research, excessive NLRP3 activation can exacerbate cardiac inflammation, increasing the release of IL-1β and IL-18, inducing cardiomyocyte apoptosis, and contributing to myocardial hypertrophy and fibrosis. Existing evidence suggests that limiting NLRP3 activity facilitates recovery in damaged cardiac tissue. Therefore, maintaining balanced pyroptosis activation is beneficial for cancer therapy, particularly in hematologic malignancies. Nonetheless, further research is needed to identify the optimal equilibrium for pyroptosis induction to avoid associated cardiovascular toxicity. CQ and HCQ directly affect the electrophysiological properties of cardiomyocytes, significantly influencing heart rhythm and causing QT interval prolongation—a risk exacerbated when combined with antiarrhythmic drugs (Kim et al., 2020; Sutanto and Heijman, 2020). This stems from their direct impact on potassium and calcium ion channels, prolonging myocardial repolarization and increasing intracellular calcium concentration. Additionally, these drugs exert significant effects on cardiomyocyte structure and metabolism: studies show that CQ and HCQ interfere with myocardial β-oxidation, promote intracellular fatty acid accumulation, disrupt cardiac energy supply, and induce myocardial cell damage (; Sutanto and Heijman, 2020).
Conclusion and prospect
PCD has emerged as a crucial strategy in anti-tumor drug development. PCD encompasses diverse modalities such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis, each with distinct molecular regulatory networks and hallmarks. Apoptosis, a caspase-dependent process, is regulated by endogenous, exogenous, and ER stress-induced pathways. Necroptosis is caspase-independent and involves RIPK1, RIPK3, and MLKL. Pyroptosis is pro-inflammatory and executed via canonical or non-canonical pathways. Autophagy is a lysosome-mediated process for intracellular component recycling, with macroautophagy, microautophagy, and CMA as subtypes. Ferroptosis is characterized by iron-dependent lipid peroxidation, and cuproptosis is copper-dependent.
Many anti-tumor agents, including chemotherapeutics, targeted drugs, and immune checkpoint inhibitors, exert effects through modulating PCD pathways. However, these agents are associated with significant cardiovascular risks. For example, anthracyclines cause cardiomyocyte damage through free radical generation; HER2 inhibitors disrupt cardiomyocyte survival pathways; ICIs can trigger myocarditis and cytokine storms. Necroptosis in tumors has a dual role, and its induction may carry cardiotoxic risks. Pyroptosis can both promote and suppress tumorigenesis, and excessive activation in the cardiovascular system can lead to cardiac inflammation. Autophagy-targeting drugs like CQ and HCQ have cardiovascular side effects such as QT interval prolongation and myocardial cell damage. Ferroptosis induction can enhance the efficacy of conventional cancer therapies, but the associated cardiovascular risks need to be further explored.
Future research is needed to comprehensively understand the complex interplay between different PCD pathways and cardiovascular biology. This will facilitate the development of more effective and safer cancer therapies. Strategies could include designing drugs that specifically target PCD pathways in tumor cells while minimizing cardiovascular toxicity. Additionally, personalized medicine approaches may be developed, considering individual patient’s genetic profiles and cardiovascular status to optimize treatment regimens. Moreover, exploring novel combinations of therapies that synergistically induce PCD in tumors while protecting the cardiovascular system holds great promise for improving cancer treatment outcomes.
Statements
Author contributions
TY: Conceptualization, Writing – original draft, Investigation, Formal Analysis, Methodology. DZ: Writing – original draft, Formal Analysis, Methodology. JY: Formal Analysis, Investigation, Writing – review and editing. JiH: Formal Analysis, Conceptualization, Writing – review and editing. JuH: Formal Analysis, Conceptualization, Supervision, Methodology, Funding acquisition, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Natural Science Foundation of China (81900339), The Third People’s Hospital of Chengdu First-Class Incubation Project (CSY-YN-01-2023-003).
Conflict of interest
The authors declare that the research 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) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
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References
1
AlexandreJ.CautelaJ.EderhyS.DamajG. L.SalemJ. E.BarlesiF.et al (2020). Cardiovascular toxicity related to cancer treatment: a pragmatic approach to the American and european cardio-oncology guidelines. J. Am. Heart Assoc.9 (18), e018403. 10.1161/jaha.120.018403
2
AlruwailiM.JarrarB.JarrarQ.AlruwailiM.GohK. W.MoshawihS.et al (2023). Hydroxychloroquine toxicity in the vital organs of the body: in vivo study. Front. Biosci. Landmark Ed.28 (7), 137. 10.31083/j.fbl2807137
3
AndersonA. C.JollerN.KuchrooV. K. (2016). Lag-3, Tim-3, and TIGIT: co-Inhibitory receptors with specialized functions in immune regulation. Immunity44 (5), 989–1004. 10.1016/j.immuni.2016.05.001
4
BaasP.ScherpereelA.NowakA. K.FujimotoN.PetersS.TsaoA. S.et al (2021). First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (checkMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet397 (10272), 375–386. 10.1016/s0140-6736(20)32714-8
5
BalletV.BohmeG. A.BrohanE.BoukaibaR.ChambardJ. M.Angouillant-BonifaceO.et al (2022). In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine. Eur. J. Pharmacol.915, 174670. 10.1016/j.ejphar.2021.174670
6
BealA. M.BertinJ.ReillyM. A. (2018). Use of RIP1 kinase small-molecule inhibitors in studying necroptosis. Methods Mol. Biol.1857, 109–124. 10.1007/978-1-4939-8754-2_11
7
BerthelootD.LatzE.FranklinB. S. (2021). Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol. Immunol.18 (5), 1106–1121. 10.1038/s41423-020-00630-3
8
BertrandM. J.MilutinovicS.DicksonK. M.HoW. C.BoudreaultA.DurkinJ.et al (2008). cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell30 (6), 689–700. 10.1016/j.molcel.2008.05.014
9
BüyükçelikA.OnurH.AkbulutH.BülentY.EnsariA.UtkanG.et al (2005). Expression of p53 protein and DNA flow cytometry in gastric adenocarcinoma: implications in patients treated with adjuvant etoposide, adriamycin and cisplatin. Tumori91 (4), 302–308. 10.1177/030089160509100403
10
CaiF.LuisM. A. F.LinX.WangM.CaiL.CenC.et al (2019). Anthracycline-induced cardiotoxicity in the chemotherapy treatment of breast cancer: preventive strategies and treatment. Mol. Clin. Oncol.11 (1), 15–23. 10.3892/mco.2019.1854
11
CaiW.XuD.ZengC.LiaoF.LiR.LinY.et al (2022). Modulating lysine crotonylation in cardiomyocytes improves myocardial outcomes. Circ. Res.131 (5), 456–472. 10.1161/circresaha.122.321054
12
CarlinoM. S.LarkinJ.LongG. V. (2021). Immune checkpoint inhibitors in melanoma. Lancet398 (10304), 1002–1014. 10.1016/s0140-6736(21)01206-x
13
CarneiroB. A.El-DeiryW. S. (2020). Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol.17 (7), 395–417. 10.1038/s41571-020-0341-y
14
CejasR. B.PetrykeyK.SapkotaY.BurridgeP. W. (2024). Anthracycline toxicity: light at the end of the tunnel?Annu. Rev. Pharmacol. Toxicol.64, 115–134. 10.1146/annurev-pharmtox-022823-035521
15
ChangY. Y.WangM.YehJ. H.TsouS. C.ChenT. C.HsuM. Y.et al (2023). The protective effects of beta-mangostin against sodium iodate-induced retinal ROS-mediated apoptosis through MEK/ERK and p53 signaling pathways. Food Funct.14 (24), 10896–10909. 10.1039/d3fo03568a
16
ChenS.GuanS.YanZ.OuyangF.LiS.LiuL.et al (2023). Role of RIPK3‑CaMKII‑mPTP signaling pathway‑mediated necroptosis in cardiovascular diseases (review). Int. J. Mol. Med.52 (4), 98. 10.3892/ijmm.2023.5301
17
ChenZ.ZouY.ZhangY.ChenZ.WuF.JinH.et al (2022). A pyroptosis-based prognostic model for immune microenvironment estimation of hepatocellular carcinoma. Dis. Markers2022, 8109771. 10.1155/2022/8109771
18
ChengJ.HeS.WangM.ZhouL.ZhangZ.FengX.et al (2019). The Caspase-3/PKCδ/Akt/VEGF-A signaling pathway mediates tumor repopulation during radiotherapy. Clin. Cancer Res.25 (12), 3732–3743. 10.1158/1078-0432.Ccr-18-3001
19
ChowE. J.AggarwalS.DoodyD. R.AplencR.ArmenianS. H.BakerK. S.et al (2023). Dexrazoxane and long-term heart function in survivors of childhood cancer. J. Clin. Oncol.41 (12), 2248–2257. 10.1200/jco.22.02423
20
ChristgenS.ZhengM.KesavardhanaS.KarkiR.MalireddiR. K. S.BanothB.et al (2020). Identification of the PANoptosome: a molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis). Front. Cell Infect. Microbiol.10, 237. 10.3389/fcimb.2020.00237
21
ConlonT. M.John-SchusterG.HeideD.PfisterD.LehmannM.HuY.et al (2020). Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature588 (7836), 151–156. 10.1038/s41586-020-2882-8
22
CuriglianoG.MayerE. L.BursteinH. J.WinerE. P.GoldhirschA. (2010). Cardiac toxicity from systemic cancer therapy: a comprehensive review. Prog. Cardiovasc Dis.53 (2), 94–104. 10.1016/j.pcad.2010.05.006
23
D'ArcyM. S. (2019). Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int.43 (6), 582–592. 10.1002/cbin.11137
24
DasT.AnandU.PandeyS. K.AshbyC. R.Jr.AssarafY. G.ChenZ. S.et al (2021). Therapeutic strategies to overcome taxane resistance in cancer. Drug Resist Updat55, 100754. 10.1016/j.drup.2021.100754
25
DempkeW. C. M.ZielinskiR.WinklerC.SilbermanS.ReutherS.PriebeW. (2023). Anthracycline-induced cardiotoxicity - are we about to clear this hurdle?Eur. J. Cancer185, 94–104. 10.1016/j.ejca.2023.02.019
26
DevarajanE.SahinA. A.ChenJ. S.KrishnamurthyR. R.AggarwalN.BrunA. M.et al (2002). Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene21 (57), 8843–8851. 10.1038/sj.onc.1206044
27
DikicI.ElazarZ. (2018). Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol.19 (6), 349–364. 10.1038/s41580-018-0003-4
28
DiNardoC. D.JonasB. A.PullarkatV.ThirmanM. J.GarciaJ. S.WeiA. H.et al (2020). Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl. J. Med.383 (7), 617–629. 10.1056/NEJMoa2012971
29
DingT.WangY.MengY.WuE.ShaoQ.LinS.et al (2024). Reciprocal interaction with neutrophils facilitates cutaneous accumulation of liposomes. ACS Nano18 (28), 18769–18784. 10.1021/acsnano.4c06638
30
DixonS. J.LembergK. M.LamprechtM. R.SkoutaR.ZaitsevE. M.GleasonC. E.et al (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell149 (5), 1060–1072. 10.1016/j.cell.2012.03.042
31
EmamiA. H.AlizadehaslA.SayadM.ShavandiF.FiroozbakhshP.MeshgiS.et al (2024). Diagnosis and management of cancer therapy-related myocarditis in a young female: a case report and review of literature. BMC Cardiovasc Disord.24 (1), 299. 10.1186/s12872-024-03960-6
32
FangY.TianS.PanY.LiW.WangQ.TangY.et al (2020). Pyroptosis: a new frontier in cancer. Biomed. Pharmacother.121, 109595. 10.1016/j.biopha.2019.109595
33
FanouriakisA.TziolosN.BertsiasG.BoumpasD. T. (2021). Update οn the diagnosis and management of systemic lupus erythematosus. Ann. Rheum. Dis.80 (1), 14–25. 10.1136/annrheumdis-2020-218272
34
FengX.SongQ.YuA.TangH.PengZ.WangX. (2015). Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma62 (4), 592–601. 10.4149/neo_2015_071
35
FerreiraP. M. P.SousaR. W. R.FerreiraJ. R. O.MilitãoG. C. G.BezerraD. P. (2021). Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms. Pharmacol. Res.168, 105582. 10.1016/j.phrs.2021.105582
36
FriesenC.FuldaS.DebatinK. M. (1997). Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia11 (11), 1833–1841. 10.1038/sj.leu.2400827
37
FuldaS.LosM.FriesenC.DebatinK. M. (1998). Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. Int. J. Cancer76 (1), 105–114. 10.1002/(sici)1097-0215(19980330)76:1<105::aid-ijc17>3.0.co;2-b
38
GaoP.CaoM.JiangX.WangX.ZhangG.TangX.et al (2023). Cannabinoid receptor 2-Centric molecular feedback loop drives necroptosis in diabetic heart injuries. Circulation147 (2), 158–174. 10.1161/circulationaha.122.059304
39
GaoW.WangX.ZhouY.WangX.YuY. (2022). Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct. Target Ther.7 (1), 196. 10.1038/s41392-022-01046-3
40
GeserickP.WangJ.SchillingR.HornS.HarrisP. A.BertinJ.et al (2015). Absence of RIPK3 predicts necroptosis resistance in malignant melanoma. Cell Death Dis.6 (9), e1884. 10.1038/cddis.2015.240
41
GhoshC.LuongG.SunY. (2021). A snapshot of the PD-1/PD-L1 pathway. J. Cancer12 (9), 2735–2746. 10.7150/jca.57334
42
GlickD.BarthS.MacleodK. F. (2010). Autophagy: cellular and molecular mechanisms. J. Pathol.221 (1), 3–12. 10.1002/path.2697
43
GongY.FanZ.LuoG.YangC.HuangQ.FanK.et al (2019). The role of necroptosis in cancer biology and therapy. Mol. Cancer18 (1), 100. 10.1186/s12943-019-1029-8
44
GoolsbyC.PaniaguaM.TallmanM.GartenhausR. B. (2005). Bcl-2 regulatory pathway is functional in chronic lymphocytic leukemia. Cytom. B Clin. Cytom.63 (1), 36–46. 10.1002/cyto.b.20034
45
HageC.HovesS.StraussL.BissingerS.PrinzY.PöschingerT.et al (2019). Sorafenib induces pyroptosis in macrophages and triggers natural killer cell-mediated cytotoxicity against hepatocellular carcinoma. Hepatology70 (4), 1280–1297. 10.1002/hep.30666
46
HanahanD.WeinbergR. A. (2011). Hallmarks of cancer: the next generation. Cell144 (5), 646–674. 10.1016/j.cell.2011.02.013
47
HashimotoM.ArakiK.CardenasM. A.LiP.JadhavR. R.KissickH. T.et al (2022). PD-1 combination therapy with IL-2 modifies CD8(+) T cell exhaustion program. Nature610 (7930), 173–181. 10.1038/s41586-022-05257-0
48
HeJ.DingH.LiH.PanZ.ChenQ. (2021). Intra-tumoral expression of SLC7A11 is associated with immune microenvironment, drug resistance, and prognosis in cancers: a pan-cancer analysis. Front. Genet.12, 770857. 10.3389/fgene.2021.770857
49
HighleyM. S.LanduytB.PrenenH.HarperP. G.De BruijnE. A. (2022). The nitrogen mustards. Pharmacol. Rev.74 (3), 552–599. 10.1124/pharmrev.120.000121
50
HirschhornT.StockwellB. R. (2019). The development of the concept of ferroptosis. Free Radic. Biol. Med.133, 130–143. 10.1016/j.freeradbiomed.2018.09.043
51
HofT.ChaigneS.RécaldeA.SalléL.BretteF.GuinamardR. (2019). Transient receptor potential channels in cardiac health and disease. Nat. Rev. Cardiol.16 (6), 344–360. 10.1038/s41569-018-0145-2
52
HsuS. K.LiC. Y.LinI. L.SyueW. J.ChenY. F.ChengK. C.et al (2021). Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment. Theranostics11 (18), 8813–8835. 10.7150/thno.62521
53
HuH.TianM.DingC.YuS. (2018). The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front. Immunol.9, 3083. 10.3389/fimmu.2018.03083
54
HuangC.GuoY.LiT.SunG.YangJ.WangY.et al (2024). Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy. Redox Biol.70, 103024. 10.1016/j.redox.2023.103024
55
HulstM. B.GrocholskiT.NeefjesJ. J. C.van WezelG. P.Metsä-KeteläM. (2022). Anthracyclines: biosynthesis, engineering and clinical applications. Nat. Prod. Rep.39 (4), 814–841. 10.1039/d1np00059d
56
JiangX.StockwellB. R.ConradM. (2021). Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol.22 (4), 266–282. 10.1038/s41580-020-00324-8
57
Jiménez-GuerreroR.GascaJ.FloresM. L.Pérez-ValderramaB.Tejera-ParradoC.MedinaR.et al (2018). Obatoclax and paclitaxel synergistically induce apoptosis and overcome paclitaxel resistance in urothelial cancer cells. Cancers (Basel)10 (12), 490. 10.3390/cancers10120490
58
JungS. E.AhnJ. S.KimY. H.KimS. M.UmT. G.KimB. J.et al (2021). Inhibition of Caspase-8 activity improves freezing efficiency of Male germline stem cells in mice. Biopreserv Biobank19 (6), 493–502. 10.1089/bio.2021.0017
59
KaufmanJ. L.GasparettoC.SchjesvoldF. H.MoreauP.TouzeauC.FaconT.et al (2021). Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma. Am. J. Hematol.96 (4), 418–427. 10.1002/ajh.26083
60
KciukM.GielecińskaA.Kałuzińska-KołatŻ.YahyaE. B.KontekR. (2024). Ferroptosis and cuproptosis: metal-dependent cell death pathways activated in response to classical chemotherapy - significance for cancer treatment?Biochim. Biophys. Acta Rev. Cancer1879 (4), 189124. 10.1016/j.bbcan.2024.189124
61
KesavardhanaS.MalireddiR. K. S.KannegantiT. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annu. Rev. Immunol.38, 567–595. 10.1146/annurev-immunol-073119-095439
62
KimC. W.ChoiK. C. (2021). Effects of anticancer drugs on the cardiac mitochondrial toxicity and their underlying mechanisms for novel cardiac protective strategies. Life Sci.277, 119607. 10.1016/j.lfs.2021.119607
63
KimY. S.LeeS. Y.YoonJ. W.KimD.YuS.KimJ. S.et al (2020). Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes. BMB Rep.53 (10), 545–550. 10.5483/BMBRep.2020.53.10.165
64
KirkhamA. A.PituskinE.ThompsonR. B.MackeyJ. R.KoshmanS. L.JassalD.et al (2022). Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial. Eur. Heart J. Cardiovasc Pharmacother.8 (2), 130–139. 10.1093/ehjcvp/pvab016
65
KreherM. A.KondaS.NolandM. M. B.LongoM. I.Valdes-RodriguezR. (2023). Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part II: methotrexate, alkylating agents, biologics, and small molecule inhibitors. J. Am. Acad. Dermatol88 (3), 534–542. 10.1016/j.jaad.2022.11.043
66
KulkarniM.HardwickJ. M. (2023). Programmed cell death in unicellular versus multicellular organisms. Annu. Rev. Genet.57, 435–459. 10.1146/annurev-genet-033123-095833
67
KunacN.ŠundovŽ.VilovićK. (2019). Apoptosis as a prognostic factor in colorectal carcinoma: comparison of TUNEL method and immunohistochemical expression of Caspase-3. Appl. Immunohistochem. Mol. Morphol.27 (3), e22–e27. 10.1097/pai.0000000000000623
68
LangX.GreenM. D.WangW.YuJ.ChoiJ. E.JiangL.et al (2019). Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov.9 (12), 1673–1685. 10.1158/2159-8290.Cd-19-0338
69
LevyJ. M. M.TowersC. G.ThorburnA. (2017). Targeting autophagy in cancer. Nat. Rev. Cancer17 (9), 528–542. 10.1038/nrc.2017.53
70
LiD.LiY. (2020). The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct. Target Ther.5 (1), 108. 10.1038/s41392-020-00216-5
71
LiS.SunY.SongM.SongY.FangY.ZhangQ.et al (2021). NLRP3/caspase-1/GSDMD-mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression. JCI Insight6 (23), e146852. 10.1172/jci.insight.146852
72
LinS.YuL.SongX.BiJ.JiangL.WangY.et al (2022). Correction: intrinsic adriamycin resistance in p53-mutated breast cancer is related to the miR-30c/FANCF/REV1-mediated DNA damage response. Cell Death Dis.13 (1), 82. 10.1038/s41419-022-04543-z
73
LiuT.ZhuC.ChenX.GuanG.ZouC.ShenS.et al (2022). Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance. Neuro Oncol.24 (7), 1113–1125. 10.1093/neuonc/noac033
74
LuT. F.SunL.ShihY. H.ChenY. F.FanC. T.WangS. J.et al (2025). A retrospective study evaluating the effect of trastuzumab addition to carboplatin/paclitaxel on overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma. BMC Med.23 (1), 99. 10.1186/s12916-025-03916-3
75
MartensS.BridelanceJ.RoelandtR.VandenabeeleP.TakahashiN. (2021). MLKL in cancer: more than a necroptosis regulator. Cell Death Differ.28 (6), 1757–1772. 10.1038/s41418-021-00785-0
76
Mohamad AnuarN. N.Nor HisamN. S.LiewS. L.UgusmanA. (2020). Clinical review: Navitoclax as a pro-apoptotic and anti-fibrotic agent. Front. Pharmacol.11, 564108. 10.3389/fphar.2020.564108
77
MoscaL.IlariA.FaziF.AssarafY. G.ColottiG. (2021). Taxanes in cancer treatment: activity, chemoresistance and its overcoming. Drug Resist Updat54, 100742. 10.1016/j.drup.2020.100742
78
NajafovA.ChenH.YuanJ. (2017). Necroptosis and cancer. Trends Cancer3 (4), 294–301. 10.1016/j.trecan.2017.03.002
79
NuguesA. L.El BouazzatiH.HétuinD.BerthonC.LoyensA.BertrandE.et al (2014). RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell Death Dis.5 (8), e1384. 10.1038/cddis.2014.347
80
OakninA.GladieffL.Martínez-GarcíaJ.VillacampaG.TakekumaM.De GiorgiU.et al (2024). Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet403 (10421), 31–43. 10.1016/s0140-6736(23)02405-4
81
ObengE. (2021). Apoptosis (programmed cell death) and its signals - a review. Braz J. Biol.81 (4), 1133–1143. 10.1590/1519-6984.228437
82
PanY.WangC.ZhouW.ShiY.MengX.MuhammadY.et al (2024). Inhibiting AGTR1 reduces AML burden and protects the heart from cardiotoxicity in mouse models. Sci. Transl. Med.16 (752), eadl5931. 10.1126/scitranslmed.adl5931
83
PanopoulosS.MavrogeniS.VlachopoulosC.SfikakisP. P. (2023). Cardiac magnetic resonance imaging before and after therapeutic interventions for systemic sclerosis-associated myocarditis. Rheumatol. Oxf.62 (4), 1535–1542. 10.1093/rheumatology/keac504
84
PearsonA. N.CarmichealJ.JiangL.LeiY. L.GreenM. D. (2021). Contribution of lipid oxidation and ferroptosis to radiotherapy efficacy. Int. J. Mol. Sci.22 (22), 12603. 10.3390/ijms222212603
85
PengF.LiaoM.QinR.ZhuS.PengC.FuL.et al (2022). Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct. Target Ther.7 (1), 286. 10.1038/s41392-022-01110-y
86
PengL.YangD.WengC. (2024). Sintilimab and cardiovascular toxicity. Jama331 (15), 1333–1334. 10.1001/jama.2024.0673
87
PollackS. M.RedmanM. W.BakerK. K.WagnerM. J.SchroederB. A.LoggersE. T.et al (2020). Assessment of doxorubicin and pembrolizumab in patients with advanced anthracycline-naive sarcoma: a phase 1/2 nonrandomized clinical trial. JAMA Oncol.6 (11), 1778–1782. 10.1001/jamaoncol.2020.3689
88
PorterC.AzamT. U.MohananeyD.KumarR.ChuJ.LenihanD.et al (2022). Permissive cardiotoxicity: the clinical crucible of cardio-oncology. JACC CardioOncol4 (3), 302–312. 10.1016/j.jaccao.2022.07.005
89
PudilR.MuellerC.ČelutkienėJ.HenriksenP. A.LenihanD.DentS.et al (2020). Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the cardio-oncology study group of the heart failure association and the cardio-oncology council of the european society of cardiology. Eur. J. Heart Fail22 (11), 1966–1983. 10.1002/ejhf.2017
90
PullarkatV. A.LacayoN. J.JabbourE.RubnitzJ. E.BajelA.LaetschT. W.et al (2021). Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov.11 (6), 1440–1453. 10.1158/2159-8290.Cd-20-1465
91
QinX.MaD.TanY. X.WangH. Y.CaiZ. (2019). The role of necroptosis in cancer: a double-edged sword?Biochim. Biophys. Acta Rev. Cancer1871 (2), 259–266. 10.1016/j.bbcan.2019.01.006
92
RadiZ. A.StewartZ. S.O'NeilS. P. (2018). Accidental and programmed cell death in investigative and toxicologic pathology. Curr. Protoc. Toxicol.76 (1), e51. 10.1002/cptx.51
93
RathkopfD. E.PatelM. R.ChoudhuryA. D.RascoD.LakhaniN.HawleyJ. E.et al (2025). Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer. Ann. Oncol.36 (1), 76–88. 10.1016/j.annonc.2024.09.005
94
RittmeyerA.BarlesiF.WaterkampD.ParkK.CiardielloF.von PawelJ.et al (2017). Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet389 (10066), 255–265. 10.1016/s0140-6736(16)32517-x
95
SangaranP. G.IbrahimZ. A.ChikZ.MohamedZ.AhmadianiA. (2021). LPS preconditioning attenuates apoptosis mechanism by inhibiting NF-κB and Caspase-3 activity: TLR4 pre-activation in the signaling pathway of LPS-induced neuroprotection. Mol. Neurobiol.58 (5), 2407–2422. 10.1007/s12035-020-02227-3
96
SarhanJ.LiuB. C.MuendleinH. I.LiP.NilsonR.TangA. Y.et al (2018). Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during yersinia infection. Proc. Natl. Acad. Sci. U. S. A.115 (46), E10888–e10897. 10.1073/pnas.1809548115
97
SayourN. V.Paál ÁM.AmeriP.MeijersW. C.MinottiG.AndreadouI.et al (2024). Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence. Eur. Heart J.45 (14), 1224–1240. 10.1093/eurheartj/ehae105
98
ShenS.HeF.ChengC.XuB.ShengJ. (2021). Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway. Biomed. Pharmacother.133, 110990. 10.1016/j.biopha.2020.110990
99
ShiJ.GaoW.ShaoF. (2017). Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci.42 (4), 245–254. 10.1016/j.tibs.2016.10.004
100
ShiJ.ZhaoY.WangK.ShiX.WangY.HuangH.et al (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature526 (7575), 660–665. 10.1038/nature15514
101
SnyderA. G.OberstA. (2021). The antisocial network: cross talk between cell death programs in host defense. Annu. Rev. Immunol.39, 77–101. 10.1146/annurev-immunol-112019-072301
102
SongS.ChenQ.LiY.LeiG.ScottA.HuoL.et al (2021). Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma. Gut70 (12), 2238–2248. 10.1136/gutjnl-2020-321175
103
StollG.MaY.YangH.KeppO.ZitvogelL.KroemerG. (2017). Pro-necrotic molecules impact local immunosurveillance in human breast cancer. Oncoimmunology6 (4), e1299302. 10.1080/2162402x.2017.1299302
104
SunL.ZhaoP.ChenM.LengJ.LuanY.DuB.et al (2022). Taxanes prodrug-based nanomedicines for cancer therapy. J. Control Release348, 672–691. 10.1016/j.jconrel.2022.06.004
105
SunS. J.JiaoX. D.ChenZ. G.CaoQ.ZhuJ. H.ShenQ. R.et al (2024). Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation. Nat. Commun.15 (1), 6640. 10.1038/s41467-024-50996-5
106
SutantoH.HeijmanJ. (2020). Beta-adrenergic receptor stimulation modulates the cellular proarrhythmic effects of chloroquine and azithromycin. Front. Physiol.11, 587709. 10.3389/fphys.2020.587709
107
TaoS.GuJ.WangQ.ZhengL. (2021). Translational control of Bcl-2 promotes apoptosis of gastric carcinoma cells. BMC Cancer21 (1), 12. 10.1186/s12885-020-07711-6
108
TengJ. F.MeiQ. B.ZhouX. G.TangY.XiongR.QiuW. Q.et al (2020). Polyphyllin VI induces Caspase-1-Mediated pyroptosis via the induction of ROS/NF-κB/NLRP3/GSDMD signal axis in non-small cell lung cancer. Cancers (Basel)12 (1), 193. 10.3390/cancers12010193
109
TongX.TangR.XiaoM.XuJ.WangW.ZhangB.et al (2022). Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J. Hematol. Oncol.15 (1), 174. 10.1186/s13045-022-01392-3
110
TowerJ. (2015). Programmed cell death in aging. Ageing Res. Rev.23 (Pt A), 90–100. 10.1016/j.arr.2015.04.002
111
TsaoL. R.YoungF. D.OtaniI. M.CastellsM. C. (2022). Hypersensitivity reactions to platinum agents and taxanes. Clin. Rev. Allergy Immunol.62 (3), 432–448. 10.1007/s12016-021-08877-y
112
TsvetkovP.CoyS.PetrovaB.DreishpoonM.VermaA.AbdusamadM.et al (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science375 (6586), 1254–1261. 10.1126/science.abf0529
113
van der VoortA.van RamshorstM. S.van WerkhovenE. D.MandjesI. A.KemperI.VulinkA. J.et al (2021). Three-year Follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual ERBB2 blockade in patients with ERBB2-Positive breast cancer: a secondary analysis of the TRAIN-2 randomized, phase 3 trial. JAMA Oncol.7 (7), 978–984. 10.1001/jamaoncol.2021.1371
114
WalkerA. R.MarcucciG.YinJ.BlumW.StockW.KohlschmidtJ.et al (2021). Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (alliance). Blood Adv.5 (13), 2775–2787. 10.1182/bloodadvances.2021004233
115
WangJ.LiuS.MengX.ZhaoX.WangT.LeiZ.et al (2024). Exercise inhibits doxorubicin-induced cardiotoxicity via regulating B cells. Circ. Res.134 (5), 550–568. 10.1161/circresaha.123.323346
116
WangL.LynchC.PitrodaS. P.PiffkóA.YangK.HuserA. K.et al (2024). Radiotherapy and immunology. J. Exp. Med.221 (7), e20232101. 10.1084/jem.20232101
117
WangL. J.ChiouJ. T.LeeY. C.ChangL. S. (2022). Docetaxel-triggered SIDT2/NOX4/JNK/HuR signaling axis is associated with TNF-α-mediated apoptosis of cancer cells. Biochem. Pharmacol.195, 114865. 10.1016/j.bcp.2021.114865
118
WarrenC. F. A.Wong-BrownM. W.BowdenN. A. (2019). BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis.10 (3), 177. 10.1038/s41419-019-1407-6
119
WeiA. H.MontesinosP.IvanovV.DiNardoC. D.NovakJ.LaribiK.et al (2020). Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood135 (24), 2137–2145. 10.1182/blood.2020004856
120
WuJ.YeJ.KongW.ZhangS.ZhengY. (2020). Programmed cell death pathways in hearing loss: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif.53 (11), e12915. 10.1111/cpr.12915
121
WuY.SongY.WangR.WangT. (2023). Molecular mechanisms of tumor resistance to radiotherapy. Mol. Cancer22 (1), 96. 10.1186/s12943-023-01801-2
122
XiaoQ.LiX.LiY.WuZ.XuC.ChenZ.et al (2021). Biological drug and drug delivery-mediated immunotherapy. Acta Pharm. Sin. B11 (4), 941–960. 10.1016/j.apsb.2020.12.018
123
XiaoY.ZhangT.MaX.YangQ. C.YangL. L.YangS. C.et al (2021). Microenvironment-responsive prodrug-induced pyroptosis boosts cancer immunotherapy. Adv. Sci. (Weinh)8 (24), e2101840. 10.1002/advs.202101840
124
XieL. H.FefelovaN.PamarthiS. H.GwathmeyJ. K. (2022). Molecular mechanisms of ferroptosis and relevance to cardiovascular disease. Cells11 (17), 2726. 10.3390/cells11172726
125
XieS.SunY.ZhaoX.XiaoY.ZhouF.LinL.et al (2024). An update of the molecular mechanisms underlying anthracycline induced cardiotoxicity. Front. Pharmacol.15, 1406247. 10.3389/fphar.2024.1406247
126
XiongZ.ZhuangR. L.YuS. L.XieZ. X.PengS. R.LiZ. A.et al (2024). Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer. J. Adv. Res.10.1016/j.jare.2024.12.003
127
XuZ.ZhengM.LiuY.ZhangL.ZhangX.BaiR. (2021). Roles of TNF receptor-associated and Fas-associated death domain proteins in the apoptosis of Eimeria tenella host cells. Vet. Parasitol.290, 109351. 10.1016/j.vetpar.2021.109351
128
YanH.LuoB.WuX.GuanF.YuX.ZhaoL.et al (2021). Cisplatin induces pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in triple-negative breast cancer. Int. J. Biol. Sci.17 (10), 2606–2621. 10.7150/ijbs.60292
129
YangX.HuangC.WangH.YangK.HuangM.ZhangW.et al (2024). Multifunctional nanoparticle-loaded injectable alginate hydrogels with deep tumor penetration for enhanced chemo-immunotherapy of cancer. ACS Nano18 (28), 18604–18621. 10.1021/acsnano.4c04766
130
YangY. P.HuL. F.ZhengH. F.MaoC. J.HuW. D.XiongK. P.et al (2013). Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol. Sin.34 (5), 625–635. 10.1038/aps.2013.5
131
YosefzonY.SoteriouD.FeldmanA.KosticL.KorenE.BrownS.et al (2018). Caspase-3 regulates YAP-dependent cell proliferation and organ size. Mol. Cell70 (4), 573–587. 10.1016/j.molcel.2018.04.019
132
YouJ. H.LeeJ.RohJ. L. (2021). PGRMC1-dependent lipophagy promotes ferroptosis in paclitaxel-tolerant persister cancer cells. J. Exp. Clin. Cancer Res.40 (1), 350. 10.1186/s13046-021-02168-2
133
YuP.ZhangX.LiuN.TangL.PengC.ChenX. (2021). Pyroptosis: mechanisms and diseases. Signal Transduct. Target Ther.6 (1), 128. 10.1038/s41392-021-00507-5
134
YuanJ.OfengeimD. (2024). A guide to cell death pathways. Nat. Rev. Mol. Cell Biol.25 (5), 379–395. 10.1038/s41580-023-00689-6
135
ZhangT.ZhangY.CuiM.JinL.WangY.LvF.et al (2016). CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat. Med.22 (2), 175–182. 10.1038/nm.4017
136
ZhangY.YangX.GeX.ZhangF. (2019). Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice. Biomed. Pharmacother.109, 726–733. 10.1016/j.biopha.2018.10.161
137
ZhangZ.ZhangY.LiebermanJ. (2021). Lighting a fire: can we harness pyroptosis to ignite antitumor immunity?Cancer Immunol. Res.9 (1), 2–7. 10.1158/2326-6066.Cir-20-0525
138
ZhaoJ.JitkaewS.CaiZ.ChoksiS.LiQ.LuoJ.et al (2012). Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. U. S. A.109 (14), 5322–5327. 10.1073/pnas.1200012109
139
ZhengX.LiuB.LiuX.LiP.ZhangP.YeF.et al (2022). PERK regulates the sensitivity of hepatocellular carcinoma cells to High-LET carbon ions via either apoptosis or ferroptosis. J. Cancer13 (2), 669–680. 10.7150/jca.61622
140
ZhouQ.XiangJ.QiuN.WangY.PiaoY.ShaoS.et al (2023). Tumor abnormality-oriented nanomedicine design. Chem. Rev.123 (18), 10920–10989. 10.1021/acs.chemrev.3c00062
141
ZhouZ.HeH.WangK.ShiX.WangY.SuY.et al (2020). Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science368 (6494), eaaz7548. 10.1126/science.aaz7548
Summary
Keywords
programmed cell death, necroptosis, pyroptosis, autophagy, ferroptosis, cardiovascular risk
Citation
Yue T, Zheng D, Yang J, He J and Hou J (2025) Potential value and cardiovascular risks of programmed cell death in cancer treatment. Front. Pharmacol. 16:1615974. doi: 10.3389/fphar.2025.1615974
Received
22 April 2025
Accepted
23 June 2025
Published
03 July 2025
Volume
16 - 2025
Edited by
Lei Xi, Virginia Commonwealth University, United States
Reviewed by
Rui (Rachel) Wang, Spark Therapeutics Inc., United States
Dongze Qin, Albert Einstein College of Medicine, United States
Updates
Copyright
© 2025 Yue, Zheng, Yang, He and Hou.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jun Hou, houjun@swjtu.edu.cn
† These authors have contributed equally to this work
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