Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review

Abstract

Cancer is a complex disease characterized by specific “mission-critical” events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways—such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and—allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

1 Introduction

Cancer, an intricate disease characterized by uncontrolled cell proliferation and evasion of regulated cell death mechanisms, is a significant global health concern (Brown et al., 2023; Bhat et al., 2024). Among the several cellular mechanisms disrupted in cancer, the regulation of cell death pathways is crucial (Peng et al., 2022; Tong et al., 2022; Gong et al., 2023; Hadian and Stockwell, 2023). Programmed cell death (PCD), also known as regulated cell death (RCD), is a genetically controlled process in which cells die in an orderly manner (Koren and Fuchs, 2021; Gong et al., 2023). RCD encompasses several mechanisms, including apoptosis, necroptosis, autophagy and the newly identified pathways of pyroptosis, ferroptosis, cuproptosis, and parthanatos (Galluzzi et al., 2018) (Figure 1). Each of these mechanisms is crucial for maintaining cellular balance and responding to cellular stress (Tang et al., 2019; Lamichhane and Samir, 2023). When mammalian cells experience irreversible disruptions in their internal or external milieu, they can initiate several signal transduction cascades that ultimately result in cell death (Kayagaki et al., 2024; Newton et al., 2024). In cancer, the disruption of these pathways not only enables the initiation and progression of tumors but also significantly affects treatment resistance and patient outcomes (Table 1) (Gong et al., 2023). Each of these RCD patterns is triggered and propagated through molecular pathways that exhibit significant connectivity (Tang et al., 2019) (Figure 2). Each variant of RCD exhibits a diverse array of morphological characteristics, ranging from complete to partial programmed cell death, which elicit unique immunomodulatory properties, including anti-inflammatory effects, promotion of immune tolerance, enhancement of inflammation, and immunogenicity. Apoptosis, marked by regulated cell shrinkage and membrane blebbing, typically leads to anti-inflammatory outcomes since apoptotic cells are phagocytosed without provoking immune activation (Elmore, 2007). Autophagy is a process of cellular degradation that generally promotes cell survival; however, under prolonged stress, it can result in cell death. Autophagy can either suppress or promote inflammation based on the context, as it regulates the immune response by degrading immune modulators or releasing signals that activate immune cells (Liu et al., 2023). Necroptosis, characterized by membrane rupture and the release of cellular contents, triggers inflammation by activating immune cells via damage-associated molecular patterns (DAMPs) (Kaczmarek et al., 2013). In a similar manner, pyroptosis, characterized by pore formation and cell lysis, enhances inflammation through the release of pro-inflammatory cytokines such as IL-1β (Liu Y. et al., 2024). Cuproptosis, a form of cell death that relies on copper, inflicts damage on the mitochondria and has the potential to trigger immune responses, although its specific immunomodulatory characteristics are still under investigation (Springer et al., 2024). Ferroptosis, initiated by iron-dependent lipid peroxidation, has the potential to promote inflammation via the release of DAMPs, which in turn can affect immune responses (Qi and Peng, 2023). Parthanatos, resulting from excessive PARP activation that leads to significant DNA damage, can trigger inflammation while potentially fostering immune tolerance in chronic conditions (Huang et al., 2022). In summary, these RCD pathways influence immune dynamics by either inhibiting or facilitating immune activation, thereby affecting cancer progression and treatment results. (Galluzzi et al., 2018; Liao M. et al., 2022).

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FIGURE 2

Targeting various RCD pathways to treat cancer has been under intensive investigation for several decades (Peng et al., 2022). Research in the last decade has revealed novel RCD pathways and with these discoveries, progress has been made in clinical application to target these newly identified pathways for cancer treatment (Man et al., 2017; Seehawer et al., 2018; Zhou et al., 2021; Wang Y. et al., 2022; Zhang C. et al., 2022). Furthermore, therapeutic approaches that target these RCD pathways have been used in combination with immunotherapeutic agents to further enhance their efficacies (Tong et al., 2022). Such combined approaches have the potential to significantly improve patient outcomes. Despite notable advancements, major challenges such as treatment resistance exist. This review summarizes recent advancement in preclinical and clinical development to target RCD pathways in cancer from a therapeutic standpoint, exploring how alterations in these mechanisms contribute to cancer development and impact the efficacy of current treatment methods.

1.1 Dysregulated apoptosis in cancer and targeting strategies for therapy

Apoptosis is a vital intracellular mechanism that maintains tissue homeostasis in an organism by regulating cell populations (Elmore, 2007; Akhtar and Bokhari, 2024) (Figure 1). However, in cancer, cells lose their capacity to undergo apoptosis-induced death, which results in unchecked cell proliferation (Morana et al., 2022). Therefore, targeting the regulation of the apoptosis signaling pathway can be one of the crucial methods to improve cancer treatment (Pfeffer and Singh, 2018). Apoptosis is characterized by cell shrinkage, chromatin condensation, membrane blebbing, DNA breakage, and apoptotic body formation (Elmore, 2007). It involves two primary pathways: the extrinsic pathway, triggered by death receptors, and the intrinsic pathway, regulated by mitochondria (Zhang et al., 2005; Jan and Chaudhry, 2019) (Figure 2). The extrinsic pathways are controlled by transmembrane death receptors belonging to the CD95 (Apo-1 or Fas)/TRAIL/tumor-necrosis factor (TNF) receptor 1 family. When death ligands such as TNFα (tumor necrosis factor-alpha), Fas ligand (FasL), or TRAIL bind to their corresponding cell surface receptors—TNFR1, Fas, and death receptors 4 and 5 (DR4/5)—it triggers a signaling cascade. This ligand-receptor interaction leads to the recruitment and activation of caspase-8, an initiator caspase, which in turn activates downstream effector caspases (Annibaldi and Walczak, 2020). The mitochondrion is involved in the other primary route that is responsible for death signaling. It performs the function of an integrating sensor of numerous death insults by releasing cytochrome c into the cytosol, where it then activates caspase. It is believed that the mitochondrial route is the primary target of survival signaling pathways (Elmore, 2007). The Bcl-2 family controls the mitochondrial (intrinsic) pathway, which is triggered by damage of the mitochondria and the subsequent release of cytochrome c. This route is initiated by cytotoxic agents and UV radiation. Cytochrome c, Apaf-1, d-ATP/ATP, and procaspase-9 interact to form an apoptosome, which then triggers the caspase cascade (Wang and Youle, 2009). Additionally, a third pathway related to endoplasmic reticulum (ER) stress has also been described (Iurlaro and Munoz-Pinedo, 2016). Stress causes mutant proteins to accumulate in the endoplasmic reticulum, disrupting the balance between protein folding and protein requirement. This event triggers the unfolded protein response (UPR), which identifies and modulates ER stress (Schroder and Kaufman, 2005; Gardner et al., 2013). Key sensors in the UPR—ATF6 (activating transcription factor 6), IRE1α (inositol-requiring enzyme 1 alpha), and PERK (protein kinase R-like ER kinase)—are activated when misfolded protein concentrations exceed a certain threshold. If the stress is too severe or prolonged, the UPR can shift from a protective role to triggering apoptosis, in order to eliminate the affected cell and prevent damage (Spencer and Finnie, 2020). Despite having distinct mechanisms of initiation, these intrinsic, extrinsic and stress-induced pathways all lead to activation of a series of proteolytic enzymes that are members of the caspase family (Elmore, 2007; McIlwain et al., 2015) (Figure 2). The caspases, which are cascades of cysteine aspartyl proteases are produced as dormant zymogens, which are then activated by proteolytic cleavage. This is normally accomplished by the action of upstream apical caspases (McIlwain et al., 2015). Apart from these intrinsic, extrinsic and stress-induced processes, there exists an additional pathway that entails T cell mediated cytotoxicity and perforin/granzyme-dependent cell death. The cell death inducing enzymes in this pathway are granzyme B and granzyme A proteases (Trapani and Smyth, 2002).

Cancer cells often overexpress proteins that prevent the apoptotic cascade from being activated, including Bcl-2 and related anti-apoptotic proteins such as Bcl-xL, Mcl-1, A1/Bf1 and Bcl-w (Table 1) (Lowe and Lin, 2000). Targeting these proteins has become a strategy to inhibit cancer proliferation and promote cell death (Frenzel et al., 2009; Carneiro and El-Deiry, 2020). Developing cancer drugs targeting the apoptosis pathway represents the first phase of clinical development in the field (Jan and Chaudhry, 2019). A comprehensive list of compounds targeting apoptotic pathways and demonstrating anti-cancer properties is presented in Table 2. ABT-737 was the initial chemical inhibitor targeting Bcl-2, Bcl-xL and Bcl-w (Del Gaizo Moore et al., 2007). It binds to the hydrophobic pocket of Bcl-2 family members and has shown efficacy against lung cancer, especially when combined with chemotherapy and radiation therapy. Navitoclax (ABT-263) demonstrates anti-cancer properties, particularly when used with MEK or tyrosine kinase inhibitors against solid tumors (Tse et al., 2008; Walensky et al., 2004) (ABT-199), a potent Bcl-2 inhibitor, has shown promising outcomes for treating acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) (Souers et al., 2013). Selective Bcl-xL inhibitors include a vaccine for prostate cancer and ABBV-155, an antibody-drug conjugate being studied as monotherapy or for use in combination with taxanes for solid tumors (Walensky et al., 2004).

BH3 mimetics have been effectively created using stapled peptides that specifically bind through protein-protein interactions and have an improved ability to enter the cell (Ali et al., 2019). SAHBA (Stabilized Alpha-Helix of BCL-2 Domains) mimics the α-helical BH3 section of proapoptotic BID, efficiently enters leukemia cells, binds to Bcl-xL, and promotes apoptosis (Chang et al., 2013). Targeting Bax using small molecules like SMBA1-3, which bind directly to Bax and inhibit the phosphorylation of S184, promotes cytochrome c release and apoptosis (Li et al., 2017).

The Bcl-2 family member Mcl-1 can prevent apoptosis induced by multiple apoptotic triggers such as radiation and chemotherapy (Wertz et al., 2011; Widden and Placzek, 2021). AM-8621 attaches to the Mcl-1 binding pocket, displaces BIM and induces apoptosis in a myeloma cell line (Wei et al., 2020). Derivatives AMG 176 and AZD5991 have shown notable outcomes in combination with venetoclax and chemotherapy (Caenepeel et al., 2018; Tron et al., 2018). Mcl-1 inhibitors VU661013 and S63845 show promise in treating blood cancers and overcoming resistance to venetoclax when used in combination with other therapies (Carneiro and El-Deiry, 2020; Satta and Grant, 2020). In addition, IAP inhibitors have been used to target apoptosis in cancer (Fulda and Vucic, 2012; Monian and Jiang, 2012). Antagonists like LCL161 and birinapant (TL32711) show promising anti-tumor effects, particularly in combination with chemotherapy, radiation and the immune checkpoint inhibitor (ICI) anti-PD1 pembrolizumab (Amaravadi et al., 2015; Yang et al., 2019).

Agonist antibodies were also created targeting DR4 and DR5 due to their favorable half-life and notable preclinical efficacy (Hymowitz et al., 1999; LeBlanc and Ashkenazi, 2003). The only clinically tested anti-DR4 monoclonal antibody is mapatumumab, a completely human DR4-agonistic antibody with selective and strong binding to DR4 and high cytotoxicity (Pukac et al., 2005). Mapatumumab was tested in phase I and II clinical trials for HCC, NSCLC, colorectal cancer, and refractory non-Hodgkin’s lymphoma (Greco et al., 2008; Hotte et al., 2008; Trarbach et al., 2010; Younes et al., 2010; von Pawel et al., 2014; Ciuleanu et al., 2016), but none of the assays met the initial objectives, ending clinical development. Unlike DR4, several DR5 agonist antibodies have been developed and tested in clinic including Conatumumab, Drozitumab, Lexatumumab, LBY135, Tigatuzumab, and DS-8273a (Belyanskaya et al., 2007; Herbst et al., 2010; Kang et al., 2011; Forero-Torres et al., 2013; Burvenich et al., 2016; Dominguez et al., 2017; Forero et al., 2017). Conatumumab and Drozitumab demonstrated efficacy in advanced solid tumors, while Lexatumumab was tested in prostate and bladder cancer cells (Shimada et al., 2007; Herbst et al., 2010; Rocha Lima et al., 2012). DS-8273a is the newest clinically tested anti-DR5 antibody. The initial study showed that DS-8273a might be used to eliminate myeloid-derived suppressor cells in advanced cancer patients, but no objective response was seen (Dominguez et al., 2017). It is tested in three more clinical trials to assess its safety in advanced solid tumors and lymphomas or its efficacy in combination with Nivolumab in advanced colorectal cancer and unresectable stage II and IV melanoma (Dubuisson and Micheau, 2017). In addition, chimeric mouse–human antibodies LBY135 and Tigatuzumab were developed. Solid advanced cancers tolerated LBY135 well, and Tigatuzumab was investigated for relapsed lymphoma or solid malignancies (Forero-Torres et al., 2010; Sharma et al., 2014). Conatumumab and Drozitumumab reached phase II clinical trials, but Lexatumumab, LBY-135, and Tigatuzumab did not (Dubuisson and Micheau, 2017).

The p53 protein, a critical tumor suppressor, is often altered or deactivated in various malignancies, making it an ideal target for therapeutic treatments. Several p53-targeted medicines have been developed to help restore or improve p53 function. MDM2 inhibitors, including Nutlin-3, APG-115, RG7388, DS-3032, and MK-8242, suppress the p53-MDM2 interaction, stabilizing p53 and inducing apoptosis in malignancies such as gastric cancer and leukemia (Ding et al., 2013; Levine, 2022). Other MDM2 antagonists include AMG-232, HDM201, BI 907828, and ALRN-6924 (Carneiro and El-Deiry, 2020; Peng et al., 2022). MDMX inhibitors, such as XI-011 and DIMP53-1, restore p53 stability by inducing apoptosis and reducing migration in cervical and colon malignancies (Soares et al., 2017; Zhang J. et al., 2022). Small compounds such as PRIMA-1 (APR-017), APR-246 (Eprenetapopt), and COTI-2 restore mutant p53 to a functional state, reactivating its tumor-suppressive capabilities, with potential therapeutic uses in a variety of malignancies (Berke et al., 2022). The p53 agonist HO-3867 restores transcriptional repression in mutant p53, especially in ovarian cancer, resulting in cell death (Devor et al., 2021).

Cyclophilin A (CypA) inhibitors, such as HL001, impede MDM2-mediated p53 degradation, resulting in cell cycle arrest and death in NSCLC (Lu et al., 2017). Natural compounds such as Renieramycin T (RT) (Petsri et al., 2019) and Protopine (Son et al., 2019) stabilize p53, inducing apoptosis in lung and colon tumors, respectively, whereas Andrographolide (ANDRO) degrades mutant p53 (Sato et al., 2018). Actinomycin V and TCCP also increase p53 expression, which causes apoptosis in many cancer cells (Lin S. Q. et al., 2019; Rashmi et al., 2019). Heat-shock protein inhibitors, such as Mortaparib (Plus), reactivate p53 by disrupting its association with mortalin, causing apoptosis in colorectal and breast malignancies (Sari et al., 2021). Furtherrmore, Protoporphyrin IX (PpIX) targets both p53 and its homolog p73, which promotes apoptosis in CLL (Son et al., 2019).

Novel therapeutics include gold complexes like MC3, which upregulate p53 via the ROS formation and have shown effectiveness in colorectal cancer (Dabiri et al., 2019), as well as platinum-based compounds like bromocoumarinplatin 1 and diplatin, which activate p53 to overcome cisplatin or carboplatin resistance respectively in lung cancer (Lin X. et al., 2019; Ma et al., 2020). Other small compounds, such as DJ34, kill leukemia stem cells by inhibiting c-Myc and activating p53 (Tadele et al., 2021), whereas AQ-101 inhibits MDM2 to activate p53 and increase apoptosis in leukemia (Gu et al., 2018).

Research is exploring inhibitors of uncontrolled oncogenic effectors such as PI3K, AKT, β-catenin, Myc, CDKs, mTOR, and VEGF (Sever and Brugge, 2015). CDK4/6 inhibitors like palbociclib enhance cell death and induce cell cycle arrest in various cancers (Tao et al., 2016). Epigenetic strategies focused on inducing apoptosis in cancer cells involve histone deacetylase (HDAC) inhibitors and Bromodomain and Extra-Terminal motif (BET) inhibitors (Bolden et al., 2006; Kim et al., 2018). HDAC inhibitors, such as panobinostat, enhance Noxa expression, reduce Mcl-1 levels, and increase sensitivity to Bcl-2 inhibitors (Liu et al., 2018). They also enhance the effectiveness of MEK inhibitors and venetoclax in treating multiple myeloma (DiNardo et al., 2019). BET inhibitors like ABBV-075, when combined with venetoclax, demonstrate promising outcomes in patients with cutaneous T cell lymphoma (CTCL) (Kim et al., 2018). The hypomethylating agent azacytidine, when combined with venetoclax and ABT-737, has shown promising results (Mishra et al., 2023).

1.2 Targeting autophagy for cancer therapy

Autophagy, a critical mechanism for maintaining cellular balance by removing damaged organelles and protein aggregates, can also facilitate cell death (Liu et al., 2023). Cells can undergo autophagy-related cell death in two primary ways: autophagy-dependent cell death (ADCD) which transpires independently of other programmed death mechanisms and autophagy-mediated cell death (AMCD) that occurs when autophagy-related molecules directly engage with those implicated in forms of cell death. (Zhou et al., 2022) (Figure 1). Moreover, autophagy is linked to other cell death mechanisms, such as apoptosis, necrosis, and ferroptosis, through a variety of processes (Dunkle and He, 2011; Gordy and He, 2012; Chen et al., 2018; Liu J. et al., 2020; Peng et al., 2022) (Figure 2).

Three distinct forms of autophagy have been identified: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) (Parzych and Klionsky, 2014). Microautophagy is a form of autophagy in which lytic organelles autonomously engulf and degrade cytoplasmic components. It is essential for regulating biosynthesis, transport, metabolic adaptability, organelle remodeling, and the maintenance of cellular component quality (Saha et al., 2018). Macroautophagic autophagosomes convey cellular constituents for destruction to endosomes or lysosomes (Feng et al., 2014). Autophagy starts with an isolating membrane known as the phagophore, which encases a portion of the cytoplasm. The Atg9 protein promotes growth by supplying crucial lipid constituents. The Atg1 and Atg9 proteins, together with a phosphatidylinositol 3-kinase complex, govern this activity. In the subsequent phase, two conjugation steps transpire. The first activation entails Atg12 and the Atg7 protein. The Atg12 protein is conveyed to the Atg10 protein, leading to a covalent connection with Atg5. The Atg12-Atg5 complexes subsequently associate with the Atg16L protein. The ATG12-ATG5-ATG16L1 complex is essential for the production of autophagosomes. The second step of conjugation involves the proteins Atg3, Atg4, Atg7, and LC3. The Atg4 protease cleaves proLC3, resulting in the formation of LC3-I. Subsequently, the Atg7, Atg3, and Atg12-Atg5-Atg16L proteins are conjugated. The LC3-I protein interacts with the lipophilic phosphatidyle-thanolamine (PE) to generate the LC3-II form. These stages generate the autophagosome, which encapsulates a segment of the cytoplasm and proteins. The outer membrane of the autophagosome fuses with the lysosome to form an autophagolysosome. Lysosomal enzymes facilitate the digestion of the autophagolysosome’s inner membrane and its contents (Gomez-Virgilio et al., 2022; Liu et al., 2023). Chaperone-mediated autophagy (CMA) removes damaged proteins during fasting or oxidative stress. The chaperone complex links the protein’s target motif to facilitate lysosome trafficking. In the lysosome, the complex interacts with LAMP-2A’s cytoplasmic tail and is destroyed (Bejarano and Cuervo, 2010).

Autophagy plays a complex role in cancer, acting as both an inhibitor and promoter of tumor growth (Chavez-Dominguez et al., 2020; Nawrocki et al., 2020; Debnath et al., 2023). It can help cancer cells avoid damage induced by chemotherapeutics and promote chemoresistance (Table 1) (Nawrocki et al., 2020; Debnath et al., 2023). Preclinical research using chemotherapeutics like cyclophosphamide, imatinib, and vorinostat has shown that autophagy reduces the effectiveness of these drugs and contributes to acquired resistance (Mele et al., 2020). Furthermore, autophagy aids cancer cells in adapting to chemotherapy (Ahmadi-Dehlaghi et al., 2023).

Autophagy inhibitors have shown promise in combination with chemotherapeutic and targeted immunotherapeutic drugs (Table 3). While many prospective autophagy inhibitors are being developed, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are the only approved drugs (Wang et al., 2011). HCQ, like CQ, suppresses autophagy by blocking lysosomal acidification and autophagosome degradation but has lower toxicity (Sui et al., 2013; Cook et al., 2014; Pellegrini et al., 2014; Lee et al., 2015). A Phase II trial for muscle-invasive bladder cancer is investigating the combination of HCQ with gemcitabine and cisplatin for systemic chemotherapy (Ojha et al., 2016). Similarly, in breast cancer, HCQ combined with tamoxifen was found more effective in suppressing autophagy in estrogen-positive (ER+) cell lines (Cook et al., 2014). In renal cell carcinoma, HCQ combined with temsirolimus led to increased apoptosis by inhibiting autophagy (Lee et al., 2015). Early phase I/II trials of HCQ have focused on adult solid tumors, including pancreatic adenocarcinoma, melanoma, colorectal carcinoma, myeloma, lymphoma and renal cell carcinoma, using chemotherapy drugs such as temsirolimus, bortezomib, temozolomide, vorinostat, and doxorubicin (Llovet et al., 2008; Mahalingam et al., 2014; Rangwala et al., 2014a; Rangwala et al., 2014b; Rosenfeld et al., 2014; Vogl et al., 2014; Wolpin et al., 2014). HCQ doses ranged from 400 mg to 600 mg twice daily, showing tolerability with partial responses and stable disease in some patients (Carew and Nawrocki, 2017). For advanced solid tumors and melanoma, HCQ combined with 150 mg/m² of temozolomide showed 27% stable disease and 14% partial response in wildtype melanoma (Cheng et al., 2009; Rangwala et al., 2014b). The combination of HCQ and rapamycin, an inhibitor of mTORC1 activity, was well-tolerated in advanced solid tumor (Rangwala et al., 2014a). In myeloma, HCQ combined with bortezomib improved the efficiency of proteasome inhibitors by causing the accumulation of misfolded proteins, with 45% of patients showing stable disease. The most common adverse effects were gastrointestinal issues and cytopenias (Vogl et al., 2014).

Autophagy activation by drugs like sorafenib, a multi-tyrosine kinase mTOR inhibitor used for hepatocellular cancer, is being explored as a potential cause of drug resistance (Llovet et al., 2008). Clinical trials have investigated HCQ in hepatocellular cancer (Cheng et al., 2009) and targeted immunotherapeutic treatments, such as checkpoint inhibitors, have limited efficacy and high costs. Combining autophagy modulators like HCQ with immune checkpoint inhibitors (ICI) has the potential to improve efficacy and reduce treatment costs. Several inhibitors targeting different stages of autophagy are under investigation including inhibitors of upstream signaling molecules: SBI-0206965 (ULK1 inhibitor) (Tang et al., 2017), Spautin-1 (Beclin1 inhibitor), SAR405 (Vps18 kinase inhibitor), and gambogic acid (induces caspase-mediated cleavage of autophagy proteins) (Ishaq et al., 2014; Pasquier, 2015). Autophagy initiation inhibitors include ATG4 inhibitors NSC185058 and NSC377071, and Verteporfin (inhibits early-stage autophagosome formation) (Donohue et al., 2011; Akin et al., 2014). Lysosomal inhibitors include ROC325 (Nawrocki et al., 2019), Lys05 (Amaravadi and Winkler, 2012), DQ661 (Rebecca et al., 2017), and DC661 (Rebecca et al., 2019).

Preclinical trials have also explored autophagy’s potential to enhance radiation therapy (Kim et al., 2008; Kuwahara et al., 2011). For example, in a lung cancer mouse model, combining Z-DEVD (caspase-3 inhibitor), RAD001 (mTOR inhibitor), and irradiation induced the highest levels of autophagy and associated radiation damage. This suggests that inhibiting both apoptosis and mTOR during radiotherapy could improve outcomes in non-small cell lung cancer patients (Kim et al., 2008). Similarly, in glioma cells, autophagy induction by silver nanoparticles (AgNPs) and/or radiation was confirmed by applying 3-methyladenine (3-MA), highlighting selective autophagy as a promising therapeutic avenue for effective cancer treatment (Wu et al., 2015).

1.3 Necroptosis in cancer development and treatment

Programmed inflammatory cell death, known as necroptosis, was first identified as an alternative to apoptosis following the activation of death domain receptors (Degterev et al., 2005; Dhuriya and Sharma, 2018) (Figure 1). Necroptosis is a regulated type of necrosis that is dependent on receptor interacting kinase-1 (RIPK1) and RIPK3 phosphorylating mixed-lineage kinase-like (MLKL) (Vandenabeele et al., 2010; Sun et al., 2012; Newton et al., 2014) (Figure 2). The necroptotic process begins when RNA- and DNA-sensing molecules and cell surface death receptors including FasRs, TNFR1, IFN receptors, and TLRs are activated (Kaiser et al., 2013). There are two ways that cell death signaling continues (Pasparakis and Vandenabeele, 2015). Complex I, a survival complex that communicates via NF-kB, can be created by TNF-α. RIPK1 deubiquitination transforms the complex into apoptotic complex IIa. When caspase-8 is absent and RIPK3 is elevated, the complex forms IIb (the necrosome). The death domain-related proteins RPK1, RPK3, and Fas on this necrosome directly phosphorylate the kinase domain-like protein (MLKL) to induce necroptosis. MLKL phosphorylation forms an oligomer that punctures the plasma membrane, killing the cell. Calmodulin-dependent protein kinase and mitochondrial serine/threonine protein phosphatase II are other RIPK3 downstream effects (He et al., 2009; Cai et al., 2014; Wang et al., 2014; Murphy, 2020). Necroptotic cell death is characterized by cell membrane perforation, elevated intracellular osmotic pressure, cell rounding and swelling, organelle swelling, impaired mitochondrial activity, mitochondrial membrane potential loss, nuclear chromatin loss, and plasma membrane rupture (Dhuriya and Sharma, 2018). Plasma membrane rupture causes potassium efflux, cytokines, and chemokines, which cause inflammation and immunological responses (Dhuriya and Sharma, 2018).

Necroptosis is involved in various aspects of tumor biology, including tumor development, necrosis, metastasis and the immune response within tumors (Najafov et al., 2017; Gong et al., 2019; Yan et al., 2022; Meier et al., 2024). This cell death pathway exhibits both pro- and anti-tumorigenic effects (Ye et al., 2023). Major regulators of necroptosis are often downregulated in cancer cells, correlating with unfavorable outcomes (Table1) (Yan et al., 2022). Necroptosis has emerged as a novel target for anticancer therapy due to its significant role in tumor biology (Gong et al., 2019).

Several natural compounds and small molecule inhibitors are known to induce necroptosis in cancer cells (listed in Table 4) (Wu et al., 2020). Chloroquine increases the expression of endogenous RIPK3 in colorectal cancer cell lines, with necroptosis being the mechanism (Meng et al., 2016). Shikonin, derived from a Chinese medicinal herb, induces necroptosis in nasopharyngeal carcinoma cells by enhancing reactive oxygen species (ROS) production and increasing RIPK1, RIPK3 and MLKL expression (Liu et al., 2019). Emodin triggers necroptosis in glioma cell lines by activating the TNF/RIPK1/RIPK3 pathway (Zhou et al., 2020). Neoalbaconol (NA), a compound derived from the fungus Albatrellus confluens, has been found to trigger necroptosis by facilitating the autocrine release of TNFα through the modulation of the RIPK/NF-κB signaling pathway and RIPK3-dependent reactive oxygen species (ROS) generation (Yu et al., 2015). The steroid glycoside Ophiopogonin D induces necroptosis in prostate cancer cells by activating RIPK1 (Lu et al., 2020). Resibufogenin inhibits colorectal cancer cell line growth by increasing RIPK3 expression (Han et al., 2018). The initiation of necroptosis can also be influenced by adjusting upstream signaling pathways, such as using the sphingosine analog FTY720 (fingolimod), which triggers necroptosis in human lung cancer cells by interacting with the I2PP2A/SET oncoprotein and activating the PP2A/RIPK1 pathway (Saddoughi et al., 2013).

Nanoparticles to induce necroptosis in cancer cells is another emerging field (Mohammadinejad et al., 2019). Although the antifungal agent Shikonin shows potential, its clinical use is limited due to poor tumor specificity, low water solubility, short bloodstream half-life, and high risk of side effects on healthy tissues (Boulos et al., 2019). To address these issues, Feng et al. developed an Fe(III)-shikonin supramolecular nanomedicine (FSSN) using metal-polyphenol coordination of Fe(III) and shikonin, demonstrating improved water solubility and reduced cytotoxicity in normal cells and induced both ferroptosis and necroptosis (Feng et al., 2022). In CT26 colon cancer cells, graphene oxide nanoparticles triggered necroptosis by enhancing RIPK1, RIPK3, and HMGB1 activity (Chen et al., 2015). Similarly, selenium nanoparticles induced necroptosis in prostate adenocarcinoma cells by increasing ROS production and TNF and interferon regulatory factor 1 expression (Sonkusre, 2019). Folate-sodium alginate-cholesterol nanoparticles delivering doxorubicin and metformin achieved targeted accumulation and induced various forms of programmed cell death, including necroptosis, apoptosis, and pyroptosis in xenograft melanoma tumors (Song et al., 2021). Myricetin-loaded solid lipid nanoparticles (MYC-SLNs) enhanced necroptosis in A549 cells by increasing RIPK3 and MLKL expression without affecting apoptosis and without apparent effects on the growth and health of MRC5 cells (Alidadi et al., 2022). Ma et al. developed star-PCL-azo-PEG micelles (sPCPEG-azo) to deliver dimethyl fumarate (DMF) specifically to the colon, inducing necroptosis by eliminating GSH, increasing ROS levels and activating MAPKs (Ma Z. G. et al., 2016).

In a study conducted by Liu et al., MLKL inhibitor necrosulfonamide (NSA) was shown to significantly delay tumor growth, thus offering compelling evidence of the role necroptosis plays in promoting tumor development (Liu et al., 2016). In mice, the use of necrostatin-1, another necroptosis inhibitor, has been found to be effective in reducing colitis-associated tumorigenesis (Liu et al., 2015). There is ongoing testing of the RIPK1 inhibitor, GSK2982772, in phase 2a clinical studies for individuals with inflammatory disease. Furthermore, in a clinical trial (NCT04739618), researchers explored the potential benefits of nonablative cryosurgical freezing-induced necroptosis followed by immunotherapeutic drug injection in metastatic solid tumors. The immunotherapy included pembrolizumab (anti-PD1), ipilimumab (anti-CTLA-4), and GM-CSF. The aim was to assess the overall response rate of radiographic changes (Tong et al., 2022). In addition, induction of apoptosis has also been shown to reverse drug resistance. Xu Zhao et al., effectively employed trichothecin to trigger necroptosis in cancers that are resistant to chemotherapy. Mechanistically, the natural secondary metabolite trichothecin significantly increased the expression of RIPK3. Subsequently, RIPK3 enhanced the phosphorylation of MLKL and activated mitochondrial energy metabolism and ROS production. This novel approach sensitizes cancer cells to cisplatin therapy (Zhao X. et al., 2021).

In addition, it has been shown that necroptosis-inducing drugs could impact the effectiveness of ICIs in individuals with cancer (Tang et al., 2020). Using a viral vaccination strategy, Hoecke et al. were able to effectively deliver the necroptosis mediator MLKL to tumor cells, resulting in the promotion of necroptotic death and the enhancement of antitumor immunity. Increased immunity directly against neo-epitopes was responsible for the potent antitumor immunity (Van Hoecke et al., 2020). In addition, the RNA editing enzyme ADAR1 has been widely recognized for its role in suppressing Z-type dsRNA, a substrate for ZBP1. This suppression mechanism leads to resistance and limited responsiveness to ICIs (Zhang T. et al., 2022). However, the small-molecule drug CBL0137 has the ability to directly induce the formation of Z-type dsDNA in cells. This in turn activates ZBP1-dependent necroptosis and effectively reverses the insensitivity to ICIs in mouse melanoma models (Zhang T. et al., 2022). In addition, cIAPs have the ability to hinder the RIPK1-dependent necroptosis process. However, this inhibition can be counteracted by Smac mimetics which then trigger the activation of the necroptotic death pathway in Burkitt’s lymphoma cell lines (Koch et al., 2021). In melanoma, the response to ICIs can be enhanced by using Smac mimetics which have a direct impact on immune cells such as B cells, MDSCs, DCs, and cytotoxic T cells (Michie et al., 2020). Based on the evidence, it appears that necroptosis could potentially be employed to enhance the readiness of the tumor microenvironment for immunotherapy.

Even with progress in necroptosis research, various obstacles impede its application in cancer treatment. The practicality of necroptosis, having potential as an alternative therapy for tumors resistant to apoptosis, continues to be debated. Hitomi et al. (2008) identified a cellular signaling network that regulated necroptosis and implicated two suppressor genes, CYLD and EDD1, and four Ras-related proteins, suggesting a role in tumorigenesis. CYLD gene mutations in tumorigenic epidermal cells promote carcinoma aggressiveness by increasing angiogenic factor production, which is crucial to epidermal cancer malignancy (Alameda et al., 2010). RIPK3 and CYLD were downregulated in CLL cells, and LEF1 represses CYLD. Together, necroptosis may be crucial to carcinogenesis (Reed, 2006). Tumor heterogeneity presents a significant challenge, as numerous cancers are deficient or have mutated for essential necroptosis regulators such as RIPK3 or MLKL, which restricts the effectiveness of necroptosis inducers. RIPK3-r, a truncated splice variation of RIPK3, was dramatically elevated in colon and lung tumors compared to matched normal tissues, suggesting that it may be a primary splice form involved in carcinogenesis, according to Yang et al. (2005). The RIPK3 gene lies on chromosome 14q11.2, which is mutated in several malignancies, including nasopharyngeal carcinoma and T cell leukemia/lymphoma (Kasof et al., 2000). In non-Hodgkin lymphoma, RIPK3 gene polymorphisms increases tumor risk (Wu et al., 2012). Furthermore, existing inducers exhibit a lack of selectivity, resulting in uncontrolled inflammation and the possibility of harming healthy tissues, which raises concerns regarding off-target effects and systemic toxicity. Necroptosis may enhance anti-tumor immunity due to its pro-inflammatory characteristics, yet it also has the potential to facilitate tumor progression by creating a pro-tumor environment. Necroptosis of tumor cells can affect the TME in a way that can contribute to tumor growth because the inflammation associated with necroptosis can stimulate cell division, genetic instability, angiogenesis and metastasis (Negroni et al., 2020). Furthermore, the restricted clinical evidence, primarily based on preclinical models, along with the unpredictable nature of necroptosis outcomes, adds to the complexity of its application. Tumors can develop resistance to necroptosis, similar to how they respond to therapies that induce apoptosis. Consequently, additional research is essential to enhance targeting specificity, reduce inflammatory risks, and confirm the efficacy of necroptosis-based treatments in clinical environments.

1.4 The roles of pyroptosis in cancer cell survival and treatment strategies

Pyroptosis is a form of RCD associated with inflammatory responses. It is triggered by human caspase-1, -3, -4, -5 (mouse caspase-11), −6, −8, and −9 and NLRP3 and has significant therapeutic implications for several malignancies due to its profound effects on the invasion, proliferation, and metastasis of tumor cells (Table 1) (Shi J. et al., 2014; Fang et al., 2020; Zheng and Li, 2020; Rao et al., 2022; Wei et al., 2022) (Figure 1). Gasdermin (GSDM) superfamily members, GSDMA-GSDME, which are essential to pyroptosis, are triggered by caspases and perforate the plasma membrane (Kayagaki et al., 2015; Shi et al., 2015; Rogers et al., 2019) (Figure 2). The characteristic features of pyroptosis in cancer involve gasdermins family protein cleavage and polymerization, both N-terminal and C-terminal junction domain cleavage, and activated N-terminal regions. The N-terminal generates a cell membrane pore by binding to membrane lipids, phosphatidylinositol, and cardiolipin, causing cell osmotic swelling, plasma membrane rupture, and death (Ding et al., 2016; Feng et al., 2018). Gasdermins create 10–20 nm holes in cell membranes, releasing cell contents slowly and potentially causing inflammatory responses. The cells become flattened eventually and create 1–5 μm apoptotic body-like protrusions. Nuclear concentration and chromatin DNA breaking occur as cells enlarge to rupture plasma membrane (Zhang et al., 2018). Pyroptotic pathway can occur either through classical or non-classical pathway in cancer. The classical pathway is activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (Chen and Nunez, 2010; Franchi et al., 2012). Cytoplasmic pattern recognition receptors (PRRs) identify them. Based on particular inputs, nod-like receptors (NLRs) or melanoma deficiency factor 2-like receptors (ALRs) produce inflammatory bodies and activate caspase-1. After Caspase-1 cleaves GSDMD, its N-terminal aggregates into cell membrane holes (Amarante-Mendes et al., 2018; Zheng D. et al., 2020) (Figure 2). Additionally, caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, which are then released via the membrane hole. The nonc-lassical pyrolytic pathway requires caspase-4/-5/-11 activation. After lipopolysaccharide (LPS) stimulates the cytoplasm, caspase-4/caspase-5/caspase-11 (the human equivalent of mouse caspase-11 caspase-4/caspase-5) can directly bind to the conserved structure of LPS, lipoprotein A, causing oligomerization, activation, and the N-terminal of GSDMD to be cleaved and localized to the cell membrane to form membrane pores (Kayagaki et al., 2015). Pyroptosis is quicker and more violent than apoptosis, releasing several pro-inflammatory molecules. Cell scorch is caused by inflammatory corpuscles and GSDM family proteins.

Several chemotherapeutic drugs, including cisplatin, paclitaxel, 5-FU, lobaplatin and others have been found to trigger pyroptosis in tumor cells (Table 5) (Zhang C. C. et al., 2019; Jia et al., 2023). Chemotherapy-induced pyroptosis is frequently the result of GSDME pathway activation. Chemotherapy drug Lobaplatin triggers pyroptosis in cervical cancer and colorectal cancer by activating GSDME (Chen et al., 2022). This effect is achieved by activating caspase-3/9 through the ROS/JNK/BAX mitochondrial apoptosis pathway (Yu et al., 2019). 5-FU triggers pyroptosis in gastric cancer cells via GSDME instead of GSDMD (Wang Y. et al., 2018). When exposed to cisplatin or 5-FU, GSDME^+/+ mice experience significant intestinal damage and infiltration of immune cells. On the other hand, GSDME^−/− mice show less injury, indicating that triggering pyroptosis in cancer cells might offer a potential alternative approach for cancer treatment (Yu and He, 2017).

Clinical trials have demonstrated that the combination of PD-L1 inhibitors with chemotherapy or radiation can effectively eliminate tumor cells through pyroptosis induction (Reck et al., 2019). This approach has shown promising results in terms of improved patient survival rates, surpassing those observed in patients solely treated with PD-L1 inhibitors. In breast cancer cells, the presence of Trimethylamine N-oxide (TMAO) can trigger GSDME-mediated pyroptosis (Wang H. et al., 2022), and when TMAO is combined with PD-1, it has the potential to enhance the antitumor effects of anti-PD-1 (Jia et al., 2023).

CAR-T cells have been successfully utilized to effectively treat hematological malignancies, yielding favorable outcomes (Gill and Brudno, 2021). However, cytokine release syndrome (CRS) is a significant side effect of this technology. When CAR-T cells release granzyme B, it can trigger pyroptosis by activating the caspase-3/GSDME pathway (Liu Y. et al., 2020). Interestingly, the elimination of GSDME through knockout has been found to effectively prevent CRS. Furthermore, the presence of perforin/granzyme B in CAR-T cells, as opposed to in CD8⁺ T cells, triggers GSDME-mediated pyroptosis in target cells (Liu Y. et al., 2020). These findings underscore the clinical importance of pyroptosis in immunotherapy. The release of IL-1β and IL-18 by pyroptotic cells, along with other DAMPs, can attract immune cells like dendritic cells (DCs) and macrophages (MFs) to engulf the pyroptotic cells (Wang Q. et al., 2018; Karki and Kanneganti, 2021). Mature DCs display tumor-specific antigens to activate cytotoxic T lymphocytes, which then eliminate tumors (Wang et al., 2013).

Targeted drugs have also been discovered that selectively trigger pyroptosis in tumor cells (Table 5). Val-boroPro triggers pyroptosis in primary acute myeloid leukemia (AML) cells by activating the inflammasome sensor protein CARD8 which then activates procaspase-1 (Johnson et al., 2018). In a melanoma study, it was found that the combination of BRAFi and MEKi could potentially have an antitumor effect by inducing pyroptosis through GSDME (Erkes et al., 2020). Additionally, the combination of DDP and BI2536 (a PLK1 kinase inhibitor) was observed to induce pyroptosis in esophageal cancer cells (Wu M. et al., 2019). In a study conducted by Dobrin et al., triple-negative breast cancer cells were exposed to ivermectin, resulting in the activation of the pannexin-1 pathway. This activation led to the overexpression of P2X4/P2X7 receptors, the release of ATP and ultimately the induction of pyroptosis (Draganov et al., 2015). Several drugs, including metformin, anthocyanin, and DHA have been found to trigger GSDMD mediated pyroptosis in different types of cancers (Pizato et al., 2018; Wang L. et al., 2019; Yue et al., 2019).

1.5 Clinical development targeting ferroptosis for cancer treatment

Ferroptosis is a recently discovered RCD pathway distinguished by oxidative and non-apoptotic mechanisms. It is characterized by iron-dependent lipid peroxide damage in mitochondria and a lack of glutathione peroxidase 4 (GPX4) and is distinct from apoptosis, autophagy, and necrosis (Dixon et al., 2012) (Figures 1, 2). From a morphological perspective, the cell membrane stays intact while developing blisters. The mitochondria decrease in size, and their membrane density increases. The mitochondrial cristae may either reduce in number or vanish entirely. The nucleus retains its typical size, while the chromatin remains uncondensed. Ferroptosis takes place when there is a disruption in the regulatory system, resulting in the buildup of lipid peroxide to a critical level. Transferrin (TF) attaches to extracellular Fe3+ and aids in its transport into cells through transferrin receptor 1 (TfR1), where it is subsequently transformed into Fe2+ (Masaldan et al., 2018). Subsequently, intracellular divalent metal transporter 1 (DMT1) and zinc transporter 8/14 (ZIP8/14) facilitate the storage of Fe2+ in the intracellular labile iron pool (LIP) (Sterling et al., 2017). Fe2+ can transfer electrons via the Fenton reaction with peroxide, leading to the generation of oxidizing free radicals. After an excessive buildup of iron within cells, many free radicals engage with polyunsaturated fatty acids (PUFA) present in the phospholipids of cell membranes, leading to the creation of lipid peroxides, which ultimately result in cell death (Doll et al., 2017). The intracellular antioxidant stress system relies on GPX4 to remove excess lipid peroxides. The Cystine/glutamate antiport (system xc−) enables the transfer of glutamate from inside cells to the exterior, while concurrently bringing cystine from outside into the cells. Inhibiting cysteine with system xc− blockers like erastin reduces the necessary cysteine levels for GSH production and disrupts GSH synthesis. GPX4 facilitates the hydrolysis of lipid peroxide through the action of GSH. Enhancing ferroptosis requires the inhibition of system Xc−, depletion of GSH, and deactivation of GPX4 (Yang et al., 2014).

Cancer cells’ higher iron (Fe) accumulation makes them more susceptible to ferroptotic cell death, thereby impacting tumor development, proliferation and metastasis (Table 1) (Maru et al., 2022; Lei et al., 2024; Zhou Q. et al., 2024). Several ferroptosis inducers have been developed, and their effectiveness varies in different cancer types (listed in Table 6) (Luo et al., 2024; Zhou Q. et al., 2024). Sorafenib, an FDA-approved chemotherapeutic for hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and thyroid cancer stimulates ferroptosis by inhibiting system XC− and glutathione (GSH) formation (Dixon et al., 2014; Sun et al., 2017). Combining sorafenib with sulfasalazine can further inhibit sulfur-based amino acid metabolism, triggering ferroptosis in HCC cells both in vitro and in vivo (Wang K. et al., 2021). In NSCLC and colon cancer, cisplatin induces ferroptosis by depleting GSH and inactivating GPX4 (Guo et al., 2018). Etoposide, a phenolic anticancer drug, depletes GSH in myeloperoxidase-rich myelogenous leukemia cells, reducing GPX4 and triggering ferroptosis (Kagan et al., 2017). Further, Ma et al. demonstrated that the combination of the lysosome disruptor siramesine with the tyrosine kinase inhibitor lapatinib resulted in the ferroptotic death of breast cancer cells. This was achieved by blocking iron transport and inducing lipid peroxidation (Ma S. et al., 2016). The combination of DHA with cisplatin triggered cell death in pancreatic ductal adenocarcinoma (PDAC) by promoting the degradation of GPX4, creation of ROS and the degradation of ferritin, leading to induction of ferroptosis (Du J. et al., 2021).

Nanotechnology enhances RCD induction by delivering inducers directly to tumors (Mohammadinejad et al., 2019). FePt@MoS2 nanoparticles, for example, release Fe(II) in the tumor microenvironment, accelerating the Fenton reaction and triggering ferroptosis in various cancer cell lines (Zhang D. et al., 2019). Similarly, additional research showed that zero-valent iron nanoparticles transformed Fe(II) to enhance the Fenton reaction, resulting in mitochondrial lipid peroxidation in oral cancer cells (Huang K. J. et al., 2019). In addition, FSSN based on the metal-polyphenol coordination of Fe(III) and shikonin, led to necroptosis and a reduced GSH level induced ferroptosis in mouse breast cancer cell lines (Feng et al., 2022).

Radiation therapy induces ferroptotic cell death by generating reactive oxygen species (ROS), leading to lipid peroxidation (Lang et al., 2019; Lei et al., 2020; Ye et al., 2020). ROS extract electrons from polyunsaturated fatty acids (PUFAs), forming lipid peroxyl radicals and hydroperoxides. Radiation also upregulates ACSL4 to facilitate PUFA-phospholipid production and also reduces GSH levels, impairing GPX4 and promoting ferroptosis (Lei et al., 2020; Ye et al., 2020; Zhang C. et al., 2022). Moreover, studies have demonstrated that disulfiram induces lysosomal membrane permeabilization through a process dependent on reactive oxygen species (ROS), leading to ferroptosis induction and enhancing the vulnerability of cells to radiation (Ye L. et al., 2021).

ICIs have advanced cancer therapy, but their efficacy is limited without tumor-associated antigens (Ding et al., 2022; Kou et al., 2023). CD8⁺ T lymphocytes can suppress tumors by triggering necroptosis, pyroptosis, and ferroptosis (Tang et al., 2020; Chen L. et al., 2021; Liao P. et al., 2022; Wang Z. et al., 2022). Unique RCDs in the TME stimulate proinflammatory cytokines and cytotoxic T cell infiltration, enhancing ICI responsiveness (Workenhe et al., 2020). Lipid peroxides generated during ferroptosis signal DCs to present tumor antigens to CD8⁺ T cells, improving immunotherapy (Zhao et al., 2022). Combining ferroptosis inducers with ICIs may enhance cancer cell susceptibility to immunotherapy. Wang and colleagues have demonstrated that the concurrent administration of a GPX4 inhibitor, cyst(e)inase, and PD-L1 inhibition enhances T cell-mediated antitumor immune responses and synergistically promotes ferroptotic death of cancer cells (Wang W. et al., 2019). On the other hand, ferroptosis inhibition therapy yielded greater antitumor efficacy when used in combination with anti-PD-1 antibodies [346].

However, ferroptosis can sometimes promote tumor initiation and progression (Dang et al., 2022). Ferroptosis-induced inflammation may drive necroinflammation-associated malignancies, and immune cell susceptibility to ferroptosis can undermine tumor suppression or promote tumor development (Bell et al., 2024). Ferroptotic cancer cells may also have immunosuppressive effects that enhance tumor growth (Chen X. et al., 2021; Qi and Peng, 2023). In addition, the ferroptosis of non-tumor cells is linked to a diminished ability to combat tumors due to a decrease in the generation of cytotoxic cytokines. Utilizing the ferroptosis inhibitor ferrostatin-1 effectively prevents CD8⁺ T cell ferroptosis by inhibiting lipid peroxidation (Wang W. et al., 2019). As a result, the production of pro-inflammatory cytokines is enhanced, leading to the elimination of tumors. Ferroptosis inhibition yields enhanced antitumor effectiveness when combined with anti-PD-1 antibodies (Ma et al., 2021). Further, Inhibiting ferroptosis could mitigate adverse effects from therapies promoting it, suggesting its suppression might be a viable cancer treatment strategy in certain contexts.

Currently, a phase II clinical study is assessing the ferroptosis inhibitor MIT-001 for preventing oral mucositis in lymphoma or multiple myeloma patients undergoing conditioning chemotherapy with autologous hematopoietic stem cell transplantation (NCT05493800).

1.6 New roles for cuproptosis in cancer cell death and targeting strategies

In 2019, Tsvetkov et al. discovered Cu-dependent death while investigating the anticancer mechanism of the Cu ionophore elesclomol (Tsvetkov et al., 2019). It was discovered that administering elesclomol to a mouse model of multiple myeloma decreased the cancer cells’ resistance to the damage caused by proteasome inhibitors. Mechanistically, reduced Cu(I) is produced when elesclomol-bound Cu(II) interacts with the mitochondrial enzyme ferredoxin 1 (FDX1), raising ROS levels (Nagai et al., 2012; Tsvetkov et al., 2019). Lipid peroxidation was once thought to be the cause of elesclomol’s lethality (Gao et al., 2021). Later, in 2022, they reported that intracellular copper build-up causes mitochondrial lipoylated protein oligomerization and destabilizes Fe–S cluster proteins, resulting in cuproptosis, an independent mode of cell death that is different from other RCD pathways (Ge et al., 2022). Research in the domains of cancer pathology and cell physiology has long focused on the role of copper in tumor progression, with studies emphasizing the critical connection between cuproptosis and cancer. Tumor angiogenesis and metastasis are activated by copper, a proangiogenic factor (Xu et al., 2022). Dysfunctional copper metabolism is the cause of both radioresistance and chemoresistance (Liu et al., 2022; Yang et al., 2022). Increased serum copper levels have been linked in a number of studies to disease invasion and tumor stage in patients with breast, lung, and colorectal cancer (Baszuk et al., 2021; Cui et al., 2021; Tsang et al., 2022). On the other hand, cuproptosis causes endothelial cell dysfunction, oxidative stress, and mitochondrial damage in malignant cells by interfering with lipid metabolism (Halliwell and Chirico, 1993; Ruiz et al., 2021).

Further, elevated Cu has been strongly associated with the increased expression level of hypoxia-inducible factor 1α (Feng et al., 2009; Wu Z. et al., 2019), inducing angiogenesis, and neovascularization leading to increased production of vascular endothelial growth factor (Zimna and Kurpisz, 2015). Elevated expression of intracellular Cu-dependent protein MEMO1, an oncogenic protein, has been associated with migration and invasion of breast and lung cancer cells (MacDonald et al., 2014). Zhang et al. have demonstrated that MEMO1 preferentially binds to Cu(I) and not Cu(II) and thus protects cells from redox activity (Zhang et al., 2022d). Consequently, releasing Cu ions and preventing the spread of tumor cells may be achieved by devising a suitable strategy to disrupt the Cu(I) binding site on the MEMO1 protein.

Cuproptosis may prevent the spread of cancer cells and reduce their proliferation (Li J. et al., 2022; Feng et al., 2024). Cuproptotic tumors exhibit reduced angiogenesis and respond well to therapy with sunitinib and sorafenib (Li K. et al., 2022). Cancer cells have developed mechanisms to defend against Cu-induced apoptosis (Table 1). For example, individuals with hepatocellular carcinoma (HCC) had significantly reduced levels of the critical cuproptosis regulator FDX1, making HCC cells resistant to cuproptosis (Zhang Z. et al., 2022). More advanced tumor-node-metastasis stages are closely linked to reduced FDX1 expression. Additionally, shorter survival rates have been associated with decreased FDX1 expression across various cancer types (Wang T. et al., 2022).

Copper ionophores, or cuproptosis-related drugs which trigger cuproptosis, may hold promise for future tumor treatments (Table 7) (Springer et al., 2024; Wang Y. et al., 2024). Elesclomol (ES) and Disulfiram (DFS) induce apoptosis by transporting copper ions into cells and mitochondria, resulting in the oligomerization of dihydrolipoamide s-acetyltransferase, decreased stability of Fe-S clusters and interaction with Npl4 (Reeder et al., 2011). Copper complexes with bis(thiosemicarbazone) ligands raise copper ion levels in both cancer cells and in Chlamydia-infected host cells (Cater et al., 2013; Marsh et al., 2017). Furthermore, derivatives of quinolines also function as copper ionophores (Oliveri et al., 2017; Oliveri, 2022). Derivatives from simple compounds such as 3-Hydroxyflavone (Dai et al., 2017), as well as more intricate copper ionophores like Hydrophilic Temperature-Sensitive Liposomes (Gaal et al., 2020) and a copper ionophore designed using salicylaldehyde isonicotinoyl hydrazone (Ji et al., 2018), also increase copper levels inside cells.

Among these agents, Elesclomol (ES) and Disulfiram (DFS) are currently undergoing evaluation in clinical trials (Xie J. et al., 2023). Recent trials investigating ES (O'Day et al., 2013) and DSF (Kelley et al., 2021) have demonstrated excellent safety profiles. Current research in this area is focused on nanomedicines that combine copper ions with copper ionophores (Lee et al., 2023; Zhou et al., 2023). Combining other cancer treatments with cuproptosis-related therapy may yield improved outcomes. Overall, copper ionophores may have greater efficacy in tumors with elevated mitochondrial metabolism. In the phase III clinical trial of ES, the impact of ES varied among individuals with low serum LDH levels (O'Day et al., 2013). Thus, serum LDH levels may serve as a prognostic indicator in the future clinical use of cuproptosis-related medications, helping to assess the potential effectiveness of these drugs. To summarize, copper ionophores can be combined with targeted therapeutic agents like TKI and PI. This combination is most effective in tumors with high mitochondrial metabolic status. Additionally, LDH can be used as a predictor to guide treatment before drug administration and as a prognostic indicator afterward. Further research is necessary to ascertain the feasibility of cuproptosis-inducing therapies in select patients with distinct types of cancer.

1.7 Parthanatos as target in cancer treatment

Parthanatos is a cell death mechanism controlled by PARP-1 and is distinct from apoptosis and necroptosis (Harraz et al., 2008) (Figures 1, 2). In parthanatos, abnormal PARP-1 activation causes excessive PAR production (Dawson and Dawson, 2004), mitochondrial membrane depolarization decreases ATP and NADPH levels, and triggers AIF translocation from mitochondria to the nucleus. Additionally, AIF binds to MIF nuclease, activating it (Wang Y. et al., 2019). After translocating to the nucleus, AIF and MIF cause nuclear shrinkage, chromatin agglutination, and big DNA fragments (15–50 KB) that cause parthanatos (Zhou et al., 2021). The lack of caspase is its main characteristic.

There is a strong correlation between parthanatos and tumor formation and progression (Zhou et al., 2021). The expression level of PARP-1 in breast cancer, ovarian cancer, endometrial cancer, lung cancer, skin cancer and non-Hodgkin’s lymphoma is elevated compared to normal tissues, thus establishing a strong association between parthanatos and these cancers (Harraz et al., 2008; Fong et al., 2009; Galia et al., 2012; Dorsam et al., 2018; Pazzaglia and Pioli, 2019). PARP-1 knockout mice showed a considerable decrease in susceptibility to epithelial malignancies. Downregulating PARP-1 protein hinders the action of NF-κB and the expression of tumor-promoting proteins controlled by NF-κB, thereby preventing the induction of parthanatos (Pazzaglia and Pioli, 2019). Additionally, the absence of PARP-1 in mice resulted in a notable decrease in the occurrence of colorectal cancer caused by oxymethane (AOM) and dextran sulfate sodium (DSS). Reducing PARP-1 protein levels may effectively prevent induced colorectal cancer by suppressing the expression of cyclin D and STAT3 (Dorsam et al., 2018).

The impact of parthanatos on carcinogenesis and tumor development manifests in two key dimensions (Zhou et al., 2021). During rapid cellular proliferation, DNA is highly susceptible to radiotherapy or chemotherapy, leading to tumor cell death. PARP-1 plays a crucial role in DNA repair and is essential for tumor cell survival. Hence, inducing apoptosis in tumor cells can be achieved by suppressing PARP-1 activity. Conversely, the occurrence of parthanatos primarily arises from the abnormal activation of PARP-1. Promoting parthanatos in tumor cells by augmenting PARP-1 activity can impede tumor cell proliferation. Given PARP-1’s involvement in several DNA repair pathways and its role in maintaining genomic stability (Yang et al., 2020), modulating PARP-1 activity may be therapeutic for treating associated malignancies (Table 8).

In clinical trials, PARP inhibitors are mostly administered to cancer patients with homologous recombination repair deficiencies including those with breast and ovarian cancers carrying BRCA1 and BRCA2 mutations (gBRCA1/2m) and castration-resistant prostate cancer. Currently, Olaparib (Clarke et al., 2024; Fenton and Hussain, 2024; Kawamoto et al., 2024; Lee et al., 2024; Shah et al., 2024), niraparib (Wu X. et al., 2024), rucaparib (Monk et al., 2022; Sayyid et al., 2024), veliparib (Mizuno et al., 2023; Rodler et al., 2023; Zhao et al., 2023; Dieras et al., 2024; Kashbour et al., 2024; Sun and Li, 2024) and talazoparib (Fizazi et al., 2024; Heiss et al., 2024; Narang et al., 2024; Piha-Paul et al., 2024; Telli et al., 2024) hinder the cancer-fighting effects of parthanatos by suppressing the catalytic function of PARP-1 and PARP-2 (Fong et al., 2009; Sandhu et al., 2013; Mateo et al., 2016; de Bono et al., 2017; Nishikawa et al., 2017; Wu X. et al., 2024).

β-Lapachone, a naturally occurring compound derived from the bark of the lapacho tree, triggers parthanatos by activating the NQO1-dependent ROS-mediated RIPK1-PARP1-AIF pathway, leading to the death of hepatocellular carcinoma cells (Zhao W. et al., 2021). This process was prevented by the inclusion of a PARP-1-specific inhibitor (Park et al., 2014). Deoxypodophyllotoxin (DPT), a naturally occurring chemical derived from Anthriscus sylvestris, effectively suppressed glioma growth by promoting the generation of excessive reactive oxygen species (ROS), enhancing PARP-1 expression and facilitating AIF translocation to the cell nucleus. This has been shown in both xenograft glioma models and in glioma cells cultured in vitro (Ma D. et al., 2016).

2 Conclusion and future perspective

The evolution of cancer therapy always involves trial and error, but discovery of novel mechanisms to target the mission-critical events shared by all tumors offers a glimpse of previously unthinkable therapeutic possibilities (Debela et al., 2021; Levantini, 2023). Understanding carcinogenesis, especially through the identification of altered cellular processes that maintain cancer cells and the development of diagnostic and prognostic biomarkers, has been made possible by studying these altered cell death pathways (Koren and Fuchs, 2021; Peng et al., 2022; Zhou Y. et al., 2024). Since RCD pathways are fundamental to the genesis of all tumors, they present clear targets for therapeutic intervention in all cancer types (Koren and Fuchs, 2021; Peng et al., 2022; Gong et al., 2023). Moreover, detecting abnormalities in these signaling pathways can aid in identifying the DNA, mRNA and protein mutations present in cancer cells, and may play a significant role in determining the efficacy of specific targeted therapies (Waarts et al., 2022; Chitluri and Emerson, 2024; Liu B. et al., 2024). While a tumor’s mutational profile may impact a therapy’s effectiveness, identifying altered RCD pathways may yield identification of novel targets.

The complexity of the cellular signaling that occurs in tumor cells presents the biggest obstacle to addressing the dysregulated pathways in distinct cancers (Bou Antoun and Chioni, 2023; Swanton et al., 2024). Crosstalk and inhibitory feedback mechanisms are just two examples of the many elements that obstruct targeted signaling pathways. Additionally, the risk of resistance selection exists with all tumor therapies and this risk may be exacerbated by the genetic plasticity present in most malignancies (Emran et al., 2022; Khan et al., 2024).

The primary therapeutic challenge in targeting RCD pathways for cancer treatment lies in the emergence of resistance mechanisms (D'Amico and De Amicis, 2024). Cancer cells often experience genetic and epigenetic changes that enable them to evade or inhibit cell death signals, even in the presence of targeted therapies designed to activate these pathways (Ozyerli-Goknar and Bagci-Onder, 2021; Tufail et al., 2024). For instance, the overexpression of anti-apoptotic proteins like BCL-2 and BCL-XL or mutations in tumor suppressors such as TP53 can inhibit apoptosis, allowing cancer cells to escape death induced by chemotherapy (Mohammad et al., 2015). In a similar vein, autophagy—a mechanism that enables cells to survive under stress—can be exploited by cancer cells to endure therapeutic damage, resulting in certain cancers, such as pancreatic and lung cancer, becoming resistant to drugs aimed at metabolic pathways (Li et al., 2019; Mele et al., 2020).

Ferroptosis, serves as another significant instance where resistance develops (Nie et al., 2022). The overexpression of GPX4, a lipid peroxidase enzyme, diminishes oxidative stress and inhibits ferroptosis-mediated cell death (Xie Y. et al., 2023), enabling cells to escape therapies aimed at triggering this type of RCD, particularly in liver and pancreatic cancers. Resistance to necroptosis, arises from the inactivation of essential regulators such as RIPK1 and RIPK3, resulting in treatment resistance in cancers including glioblastoma (Xie Y. et al., 2023) and colorectal cancer (Feng et al., 2015). In cuproptosis, cancer cells evade copper-induced cell death by disrupting copper ion homeostasis, with changes in proteins such as FDX1 and DLAT contributing to resistance in lung and melanoma cancers (Abdullah et al., 2024).

Moreover, pyroptosis, can be inhibited by the dysregulation of inflammasome components such as NLRP3 and caspase-1 (Zheng M. et al., 2020). This enables cancer cells to evade the inflammatory response typically associated with pyroptosis. This evasion mechanism has been noted in cancers including colorectal, gastric, and breast cancer. Ultimately, parthanatos, associated with the overactivation of PARP1 due to DNA damage, is often evaded in breast and ovarian cancers by the overexpression of PARP1 or mutations in related pathways, which diminishes the effectiveness of PARP inhibitors in these instances (Pazzaglia and Pioli, 2019).

These examples illustrate how cancer cells’ capacity to manipulate and resist RCD pathways complicates therapeutic strategies. The flexibility and redundancy in cell death mechanisms necessitate the creation of combination therapies or innovative strategies to re-sensitize cancer cells, highlighting the importance of addressing these resistance mechanisms across different cancers. Furthermore, recent high-throughput sequencing data demonstrate the significance of these dysregulated signaling pathways in sustaining supportive TMEs that facilitate the growth and metastasis of numerous solid tumors (Wang et al., 2023). Understanding the composition and function of the TME is thus crucial for deciphering the impact of genetic and epigenetic changes that occur in tumors and the cells that surround them. By studying various tumor types, researchers may identify common pathways that contribute to tumor development.

While the caveats associated with targeting RCD pathways for cancer therapies described above are challenging, the most effective approach to address these issues likely requires use of more advanced combination therapies that target multiple lesions unique to tumors simultaneously. Building a pathway interaction network to determine the functional dependencies between different signaling pathways may offer new perspectives on disease causes and lead to development of more effective drug formulations. Future research should place a stronger emphasis on the utilization of combination therapies for studies employing patient-derived xenografts, organoids/tumoroids and genetically modified mouse models to target oncogenic signaling pathways, RCD and the TME.

References

• 1

  AbdollahzadehH.PazhangY.ZamaniA.SharafiY. (2024). Green synthesis of copper oxide nanoparticles using walnut shell and their size dependent anticancer effects on breast and colorectal cancer cell lines. Sci. Rep.14 (1), 20323. 10.1038/s41598-024-71234-4

  • CrossRef
  • Google Scholar

• 2

  AbdullahK. M.KaushalJ. B.TakkarS.SharmaG.AlsafwaniZ. W.PothurajuR.et al (2024). Copper metabolism and cuproptosis in human malignancies: unraveling the complex interplay for therapeutic insights. Heliyon10 (5), e27496. 10.1016/j.heliyon.2024.e27496

  • CrossRef
  • Google Scholar

• 3

  AgalakovaN. I. (2024). Chloroquine and chemotherapeutic compounds in experimental cancer treatment. Int. J. Mol. Sci.25 (2), 945. 10.3390/ijms25020945

  • CrossRef
  • Google Scholar

• 4

  Ahmadi-DehlaghiF.MohammadiP.ValipourE.PournaghiP.KianiS.MansouriK. (2023). Autophagy: a challengeable paradox in cancer treatment. Cancer Med.12 (10), 11542–11569. 10.1002/cam4.5577

  • CrossRef
  • Google Scholar

• 5

  AkhtarF.BokhariS. R. A. (2024). Apoptosis. Treasure Island (FL): StatPearls.

  • Google Scholar

• 6

  AkinD.WangS. K.Habibzadegah-TariP.LawB.OstrovD.LiM.et al (2014). A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy10 (11), 2021–2035. 10.4161/auto.32229

  • CrossRef
  • Google Scholar

• 7

  AlamM.AlamS.ShamsiA.AdnanM.ElasbaliA. M.Al-SoudW. A.et al (2022). Bax/Bcl-2 cascade is regulated by the EGFR pathway: therapeutic targeting of non-small cell lung cancer. Front. Oncol.12, 869672. 10.3389/fonc.2022.869672

  • CrossRef
  • Google Scholar

• 8

  AlamedaJ. P.Moreno-MaldonadoR.NavarroM.BravoA.RamirezA.PageA.et al (2010). An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells. Oncogene29 (50), 6522–6532. 10.1038/onc.2010.378

  • CrossRef
  • Google Scholar

• 9

  AleksandrovaK. V.SuvorovaI. I. (2023). Evaluation of the effectiveness of various autophagy inhibitors in A549 cancer stem cells. Acta Naturae15 (1), 19–25. 10.32607/actanaturae.11891

  • CrossRef
  • Google Scholar

• 10

  AliA. M.AtmajJ.Van OosterwijkN.GrovesM. R.DomlingA. (2019). Stapled peptides inhibitors: a new window for target drug discovery. Comput. Struct. Biotechnol. J.17, 263–281. 10.1016/j.csbj.2019.01.012

  • CrossRef
  • Google Scholar

• 11

  AlidadiH.AshtariA.SamimiA.KaramiM. A.KhorsandiL. (2022). Myricetin loaded in solid lipid nanoparticles induces apoptosis in the HT-29 colorectal cancer cells via mitochondrial dysfunction. Mol. Biol. Rep.49 (9), 8537–8545. 10.1007/s11033-022-07683-9

  • CrossRef
  • Google Scholar

• 12

  Amarante-MendesG. P.AdjemianS.BrancoL. M.ZanettiL. C.WeinlichR.BortoluciK. R. (2018). Pattern recognition receptors and the host cell death molecular machinery. Front. Immunol.9, 2379. 10.3389/fimmu.2018.02379

  • CrossRef
  • Google Scholar

• 13

  AmaravadiR. K.SchilderR. J.MartinL. P.LevinM.GrahamM. A.WengD. E.et al (2015). A phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol. Cancer Ther.14 (11), 2569–2575. 10.1158/1535-7163.MCT-15-0475

  • CrossRef
  • Google Scholar

• 14

  AmaravadiR. K.WinklerJ. D. (2012). Lys05: a new lysosomal autophagy inhibitor. Autophagy8 (9), 1383–1384. 10.4161/auto.20958

  • CrossRef
  • Google Scholar

• 15

  AndreeffM.KellyK. R.YeeK.AssoulineS.StrairR.PopplewellL.et al (2016). Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin. Cancer Res.22 (4), 868–876. 10.1158/1078-0432.CCR-15-0481

  • CrossRef
  • Google Scholar

• 16

  AnnibaldiA.WalczakH. (2020). Death receptors and their ligands in inflammatory disease and cancer. Cold Spring Harb. Perspect. Biol.12 (9), a036384. 10.1101/cshperspect.a036384

  • CrossRef
  • Google Scholar

• 17

  Bakar-AtesF.OzkanE. (2024). Synergistic ferroptosis in triple-negative breast cancer cells: paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells. Naunyn Schmiedeb. Arch. Pharmacol. 10.1007/s00210-024-03523-8

  • CrossRef
  • Google Scholar

• 18

  BasuliD.TesfayL.DengZ.PaulB.YamamotoY.NingG.et al (2017). Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene36 (29), 4089–4099. 10.1038/onc.2017.11

  • CrossRef
  • Google Scholar

• 19

  BaszukP.MarciniakW.DerkaczR.JakubowskaA.CybulskiC.GronwaldJ.et al (2021). Blood copper levels and the occurrence of colorectal cancer in Poland. Biomedicines9 (11), 1628. 10.3390/biomedicines9111628

  • CrossRef
  • Google Scholar

• 20

  BejaranoE.CuervoA. M. (2010). Chaperone-mediated autophagy. Proc. Am. Thorac. Soc.7 (1), 29–39. 10.1513/pats.200909-102JS

  • CrossRef
  • Google Scholar

• 21

  BellH. N.StockwellB. R.ZouW. (2024). Ironing out the role of ferroptosis in immunity. Immunity57 (5), 941–956. 10.1016/j.immuni.2024.03.019

  • CrossRef
  • Google Scholar

• 22

  BelyanskayaL. L.MartiT. M.Hopkins-DonaldsonS.KurtzS.Felley-BoscoE.StahelR. A. (2007). Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin. Mol. Cancer6, 66. 10.1186/1476-4598-6-66

  • CrossRef
  • Google Scholar

• 23

  BenguiguiM.WeitzI. S.TimanerM.KanT.ShechterD.PerlmanO.et al (2019). Copper oxide nanoparticles inhibit pancreatic tumor growth primarily by targeting tumor initiating cells. Sci. Rep.9 (1), 12613. 10.1038/s41598-019-48959-8

  • CrossRef
  • Google Scholar

• 24

  BerkeT. P.SlightS. H.HyderS. M. (2022). Role of reactivating mutant p53 protein in suppressing growth and metastasis of triple-negative breast cancer. Onco Targets Ther.15, 23–30. 10.2147/OTT.S342292

  • CrossRef
  • Google Scholar

• 25

  BhatG. R.SethiI.SadidaH. Q.RahB.MirR.AlgehainyN.et al (2024). Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev.43 (1), 197–228. 10.1007/s10555-024-10172-z

  • CrossRef
  • Google Scholar

• 26

  BlagosklonnyM. V. (2023). Cancer prevention with rapamycin. Oncotarget14, 342–350. 10.18632/oncotarget.28410

  • CrossRef
  • Google Scholar

• 27

  BlockhuysS.CelauroE.HildesjoC.FeiziA.StalO.Fierro-GonzalezJ. C.et al (2017). Defining the human copper proteome and analysis of its expression variation in cancers. Metallomics9 (2), 112–123. 10.1039/c6mt00202a

  • CrossRef
  • Google Scholar

• 28

  BlockhuysS.Wittung-StafshedeP. (2017). Roles of copper-binding proteins in breast cancer. Int. J. Mol. Sci.18 (4), 871. 10.3390/ijms18040871

  • CrossRef
  • Google Scholar

• 29

  BoldenJ. E.PeartM. J.JohnstoneR. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov.5 (9), 769–784. 10.1038/nrd2133

  • CrossRef
  • Google Scholar

• 30

  BoschiA.MartiniP.Janevik-IvanovskaE.DuattiA. (2018). The emerging role of copper-64 radiopharmaceuticals as cancer theranostics. Drug Discov. Today23 (8), 1489–1501. 10.1016/j.drudis.2018.04.002

  • CrossRef
  • Google Scholar

• 31

  Bou AntounN.ChioniA. M. (2023). Dysregulated signalling pathways driving anticancer drug resistance. Int. J. Mol. Sci.24 (15), 12222. 10.3390/ijms241512222

  • CrossRef
  • Google Scholar

• 32

  BoulosJ. C.RahamaM.HegazyM. F.EfferthT. (2019). Shikonin derivatives for cancer prevention and therapy. Cancer Lett.459, 248–267. 10.1016/j.canlet.2019.04.033

  • CrossRef
  • Google Scholar

• 33

  BrewerG. J.DickR. D.GroverD. K.LeClaireV.TsengM.WichaM.et al (2000). Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin. Cancer Res.6 (1), 1–10.

  • Google Scholar

• 34

  BrownJ. S.AmendS. R.AustinR. H.GatenbyR. A.HammarlundE. U.PientaK. J. (2023). Updating the definition of cancer. Mol. Cancer Res.21 (11), 1142–1147. 10.1158/1541-7786.MCR-23-0411

  • CrossRef
  • Google Scholar

• 35

  BurvenichI. J.LeeF. T.GuoN.GanH. K.RigopoulosA.ParslowA. C.et al (2016). In vitro and in vivo evaluation of (89)Zr-DS-8273a as a theranostic for anti-death receptor 5 therapy. Theranostics6 (12), 2225–2234. 10.7150/thno.16260

  • CrossRef
  • Google Scholar

• 36

  CaenepeelS.BrownS. P.BelmontesB.MoodyG.KeeganK. S.ChuiD.et al (2018). AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov.8 (12), 1582–1597. 10.1158/2159-8290.CD-18-0387

  • CrossRef
  • Google Scholar

• 37

  CaiZ.JitkaewS.ZhaoJ.ChiangH. C.ChoksiS.LiuJ.et al (2014). Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol.16 (1), 55–65. 10.1038/ncb2883

  • CrossRef
  • Google Scholar

• 38

  CaoL.MuW. (2021). Necrostatin-1 and necroptosis inhibition: pathophysiology and therapeutic implications. Pharmacol. Res.163, 105297. 10.1016/j.phrs.2020.105297

  • CrossRef
  • Google Scholar

• 39

  CarewJ. S.NawrockiS. T. (2017). Drain the lysosome: development of the novel orally available autophagy inhibitor ROC-325. Autophagy13 (4), 765–766. 10.1080/15548627.2017.1280222

  • CrossRef
  • Google Scholar

• 40

  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

  • CrossRef
  • Google Scholar

• 41

  CaterM. A.PearsonH. B.WolyniecK.KlaverP.BilandzicM.PatersonB. M.et al (2013). Increasing intracellular bioavailable copper selectively targets prostate cancer cells. ACS Chem. Biol.8 (7), 1621–1631. 10.1021/cb400198p

  • CrossRef
  • Google Scholar

• 42

  ChanN.WillisA.KornhauserN.WardM. M.LeeS. B.NackosE.et al (2017). Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clin. Cancer Res.23 (3), 666–676. 10.1158/1078-0432.CCR-16-1326

  • CrossRef
  • Google Scholar

• 43

  ChangY. S.GravesB.GuerlavaisV.TovarC.PackmanK.ToK. H.et al (2013). Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl. Acad. Sci. U. S. A.110 (36), E3445–E3454. 10.1073/pnas.1303002110

  • CrossRef
  • Google Scholar

• 44

  ChatranM.Pilehvar-SoltanahmadiY.DadashpourM.FaramarziL.RasouliS.Jafari-GharabaghlouD.et al (2018). Synergistic anti-proliferative effects of metformin and silibinin combination on T47D breast cancer cells via hTERT and cyclin D1 inhibition. Drug Res. (Stuttg)68 (12), 710–716. 10.1055/a-0631-8046

  • CrossRef
  • Google Scholar

• 45

  Chavez-DominguezR.Perez-MedinaM.Lopez-GonzalezJ. S.Galicia-VelascoM.Aguilar-CazaresD. (2020). The double-edge sword of autophagy in cancer: from tumor suppression to pro-tumor activity. Front. Oncol.10, 578418. 10.3389/fonc.2020.578418

  • CrossRef
  • Google Scholar

• 46

  ChenG.DingX. F.BouamarH.PressleyK.SunL. Z. (2019). Everolimus induces G(1) cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells. Am. J. Physiol. Cell Physiol.317 (2), C244–C252. 10.1152/ajpcell.00390.2018

  • CrossRef
  • Google Scholar

• 47

  ChenG. Y.MengC. L.LinK. C.TuanH. Y.YangH. J.ChenC. L.et al (2015). Graphene oxide as a chemosensitizer: diverted autophagic flux, enhanced nuclear import, elevated necrosis and improved antitumor effects. Biomaterials40, 12–22. 10.1016/j.biomaterials.2014.11.034

  • CrossRef
  • Google Scholar

• 48

  ChenG. Y.NunezG. (2010). Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol.10 (12), 826–837. 10.1038/nri2873

  • CrossRef
  • Google Scholar

• 49

  ChenJ.GeL.ShiX.LiuJ.RuanH.HengD.et al (2022). Lobaplatin induces pyroptosis in cervical cancer cells via the caspase-3/GSDME pathway. Anticancer Agents Med. Chem.22 (11), 2091–2097. 10.2174/1871520621666211018100532

  • CrossRef
  • Google Scholar

• 50

  ChenL.NiuX.QiaoX.LiuS.MaH.ShiX.et al (2021a). Characterization of interplay between autophagy and ferroptosis and their synergistical roles on manipulating immunological tumor microenvironment in squamous cell carcinomas. Front. Immunol.12, 739039. 10.3389/fimmu.2021.739039

  • CrossRef
  • Google Scholar

• 51

  ChenQ.KangJ.FuC. (2018). The independence of and associations among apoptosis, autophagy, and necrosis. Signal Transduct. Target Ther.3, 18. 10.1038/s41392-018-0018-5

  • CrossRef
  • Google Scholar

• 52

  ChenX.KangR.KroemerG.TangD. (2021b). Ferroptosis in infection, inflammation, and immunity. J. Exp. Med.218 (6), e20210518. 10.1084/jem.20210518

  • CrossRef
  • Google Scholar

• 53

  ChengA. L.KangY. K.ChenZ.TsaoC. J.QinS.KimJ. S.et al (2009). Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol.10 (1), 25–34. 10.1016/S1470-2045(08)70285-7

  • CrossRef
  • Google Scholar

• 54

  ChisholmC. L.WangH.WongA. H.Vazquez-OrtizG.ChenW.XuX.et al (2016). Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin. Oncotarget7 (51), 84439–84452. 10.18632/oncotarget.12992

  • CrossRef
  • Google Scholar

• 55

  ChitluriK. K.EmersonI. A. (2024). The importance of protein domain mutations in cancer therapy. Heliyon10 (6), e27655. 10.1016/j.heliyon.2024.e27655

  • CrossRef
  • Google Scholar

• 56

  ChoiY. K.KangJ. I.HanS.KimY. R.JoJ.KangY. W.et al (2020). L-ascorbic acid inhibits breast cancer growth by inducing IRE/JNK/CHOP-related endoplasmic reticulum stress-mediated p62/SQSTM1 accumulation in the nucleus. Nutrients12 (5), 1351. 10.3390/nu12051351

  • CrossRef
  • Google Scholar

• 57

  CiuleanuT.BazinI.LungulescuD.MironL.BondarenkoI.DeptalaA.et al (2016). A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Ann. Oncol.27 (4), 680–687. 10.1093/annonc/mdw004

  • CrossRef
  • Google Scholar

• 58

  ClarkeN. W.ArmstrongA. J.OyaM.ShoreN.ProcopioG.Daniel GuedesJ.et al (2024). Efficacy and safety of olaparib plus abiraterone versus placebo plus abiraterone in the first-line treatment of patients with asymptomatic/mildly symptomatic and symptomatic metastatic castration-resistant prostate cancer: analyses from the phase 3 PROpel trial. Eur. Urol. Oncol. 10.1016/j.euo.2024.09.013

  • CrossRef
  • Google Scholar

• 59

  CluzeauT.SebertM.RahmeR.CuzzubboS.Lehmann-CheJ.MadelaineI.et al (2021). Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myelodysplasies (GFM). J. Clin. Oncol.39 (14), 1575–1583. 10.1200/JCO.20.02342

  • CrossRef
  • Google Scholar

• 60

  CookK. L.WarriA.Soto-PantojaD. R.ClarkeP. A.CruzM. I.ZwartA.et al (2014). Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin. Cancer Res.20 (12), 3222–3232. 10.1158/1078-0432.CCR-13-3227

  • CrossRef
  • Google Scholar

• 61

  CuiL.GouwA. M.LaGoryE. L.GuoS.AttarwalaN.TangY.et al (2021). Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Nat. Biotechnol.39 (3), 357–367. 10.1038/s41587-020-0707-9

  • CrossRef
  • Google Scholar

• 62

  DabiriY.Abu El MaatyM. A.ChanH. Y.WolkerJ.OttI.WolflS.et al (2019). p53-Dependent anti-proliferative and pro-apoptotic effects of a gold(I) N-heterocyclic carbene (NHC) complex in colorectal cancer cells. Front. Oncol.9, 438. 10.3389/fonc.2019.00438

  • CrossRef
  • Google Scholar

• 63

  DaiF.YanW. J.DuY. T.BaoX. Z.LiX. Z.ZhouB. (2017). Structural basis, chemical driving forces and biological implications of flavones as Cu(II) ionophores. Free Radic. Biol. Med.108, 554–563. 10.1016/j.freeradbiomed.2017.04.023

  • CrossRef
  • Google Scholar

• 64

  D'AmicoM.De AmicisF. (2024). Challenges of regulated cell death: implications for therapy resistance in cancer. Cells13 (13), 1083. 10.3390/cells13131083

  • CrossRef
  • Google Scholar

• 65

  DangQ.SunZ.WangY.WangL.LiuZ.HanX. (2022). Ferroptosis: a double-edged sword mediating immune tolerance of cancer. Cell Death Dis.13 (11), 925. 10.1038/s41419-022-05384-6

  • CrossRef
  • Google Scholar

• 66

  DawsonV. L.DawsonT. M. (2004). Deadly conversations: nuclear-mitochondrial cross-talk. J. Bioenerg. Biomembr.36 (4), 287–294. 10.1023/B:JOBB.0000041755.22613.8d

  • CrossRef
  • Google Scholar

• 67

  DebelaD. T.MuzazuS. G.HeraroK. D.NdalamaM. T.MeseleB. W.HaileD. C.et al (2021). New approaches and procedures for cancer treatment: current perspectives. SAGE Open Med.9, 20503121211034366. 10.1177/20503121211034366

  • CrossRef
  • Google Scholar

• 68

  DebnathJ.GammohN.RyanK. M. (2023). Autophagy and autophagy-related pathways in cancer. Nat. Rev. Mol. Cell Biol.24 (8), 560–575. 10.1038/s41580-023-00585-z

  • CrossRef
  • Google Scholar

• 69

  de BonoJ.RamanathanR. K.MinaL.ChughR.GlaspyJ.RafiiS.et al (2017). Phase I, dose-escalation, two-Part Trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov.7 (6), 620–629. 10.1158/2159-8290.CD-16-1250

  • CrossRef
  • Google Scholar

• 70

  DegterevA.HuangZ.BoyceM.LiY.JagtapP.MizushimaN.et al (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol.1 (2), 112–119. 10.1038/nchembio711

  • CrossRef
  • Google Scholar

• 71

  Del Gaizo MooreV.BrownJ. R.CertoM.LoveT. M.NovinaC. D.LetaiA. (2007). Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J. Clin. Invest.117 (1), 112–121. 10.1172/JCI28281

  • CrossRef
  • Google Scholar

• 72

  DengW.XiongX.LuM.HuangS.LuoY.WangY.et al (2024). Curcumin suppresses colorectal tumorigenesis through restoring the gut microbiota and metabolites. BMC Cancer24 (1), 1141. 10.1186/s12885-024-12898-z

  • CrossRef
  • Google Scholar

• 73

  DevorE. J.SchicklingB. M.LapierreJ. R.BenderD. P.Gonzalez-BosquetJ.LeslieK. K. (2021). The synthetic curcumin analog HO-3867 rescues suppression of PLAC1 expression in ovarian cancer cells. Pharm. (Basel)14 (9), 942. 10.3390/ph14090942

  • CrossRef
  • Google Scholar

• 74

  DhuriyaY. K.SharmaD. (2018). Necroptosis: a regulated inflammatory mode of cell death. J. Neuroinflammation15 (1), 199. 10.1186/s12974-018-1235-0

  • CrossRef
  • Google Scholar

• 75

  Di CosimoS.Perez-GarciaJ. M.BelletM.DalencF.Gil GilM. J.Ruiz BorregoM.et al (2023). Palbociclib with fulvestrant or letrozole in endocrine-sensitive patients with HR-positive/HER2-negative advanced breast cancer: a detailed safety analysis of the randomized parsifal trial. Oncologist28 (1), 23–32. 10.1093/oncolo/oyac205

  • CrossRef
  • Google Scholar

• 76

  DierasV.HanH. S.WildiersH.FriedlanderM.AyoubJ. P.PuhallaS. L.et al (2024). Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): final overall survival results from a randomized phase 3 trial. Eur. J. Cancer200, 113580. 10.1016/j.ejca.2024.113580

  • CrossRef
  • Google Scholar

• 77

  DilleyR. L.PohW.GladstoneD. E.HermanJ. G.ShowelM. M.KarpJ. E.et al (2014). Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro. Leuk. Res.38 (3), 411–417. 10.1016/j.leukres.2013.12.019

  • CrossRef
  • Google Scholar

• 78

  DiNardoC. D.PratzK.PullarkatV.JonasB. A.ArellanoM.BeckerP. S.et al (2019). Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood133 (1), 7–17. 10.1182/blood-2018-08-868752

  • CrossRef
  • Google Scholar

• 79

  DingJ.WangK.LiuW.SheY.SunQ.ShiJ.et al (2016). Pore-forming activity and structural autoinhibition of the gasdermin family. Nature535 (7610), 111–116. 10.1038/nature18590

  • CrossRef
  • Google Scholar

• 80

  DingP.WenL.TongF.ZhangR.HuangY.DongX. (2022). Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer. Cancer Drug Resist5 (1), 147–164. 10.20517/cdr.2021.104

  • CrossRef
  • Google Scholar

• 81

  DingQ.ZhangZ.LiuJ. J.JiangN.ZhangJ.RossT. M.et al (2013). Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem.56 (14), 5979–5983. 10.1021/jm400487c

  • CrossRef
  • Google Scholar

• 82

  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

  • CrossRef
  • Google Scholar

• 83

  DixonS. J.PatelD. N.WelschM.SkoutaR.LeeE. D.HayanoM.et al (2014). Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife3, e02523. 10.7554/eLife.02523

  • CrossRef
  • Google Scholar

• 84

  DohnerH.PratzK. W.DiNardoC. D.WeiA. H.JonasB. A.PullarkatV.et al (2024). Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine. Blood, 2024024944. 10.1182/blood.2024024944

  • CrossRef
  • Google Scholar

• 85

  DollS.PronethB.TyurinaY. Y.PanziliusE.KobayashiS.IngoldI.et al (2017). ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol.13 (1), 91–98. 10.1038/nchembio.2239

  • CrossRef
  • Google Scholar

• 86

  DominguezG. A.CondamineT.MonyS.HashimotoA.WangF.LiuQ.et al (2017). Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res.23 (12), 2942–2950. 10.1158/1078-0432.CCR-16-1784

  • CrossRef
  • Google Scholar

• 87

  DonohueE.ToveyA.VoglA. W.ArnsS.SternbergE.YoungR. N.et al (2011). Inhibition of autophagosome formation by the benzoporphyrin derivative verteporfin. J. Biol. Chem.286 (9), 7290–7300. 10.1074/jbc.M110.139915

  • CrossRef
  • Google Scholar

• 88

  DorsamB.SeiwertN.FoerschS.StrohS.NagelG.BegaliewD.et al (2018). PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. Proc. Natl. Acad. Sci. U. S. A.115 (17), E4061–E4070. 10.1073/pnas.1712345115

  • CrossRef
  • Google Scholar

• 89

  DraganovD.Gopalakrishna-PillaiS.ChenY. R.ZuckermanN.MoellerS.WangC.et al (2015). Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci. Rep.5, 16222. 10.1038/srep16222

  • CrossRef
  • Google Scholar

• 90

  DuJ.WangX.LiY.RenX.ZhouY.HuW.et al (2021a). DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism. Cell Death Dis.12 (7), 705. 10.1038/s41419-021-03996-y

  • CrossRef
  • Google Scholar

• 91

  DuY.ZhaoH. C.ZhuH. C.JinY.WangL. (2021b). Ferroptosis is involved in the anti-tumor effect of lycorine in renal cell carcinoma cells. Oncol. Lett.22 (5), 781. 10.3892/ol.2021.13042

  • CrossRef
  • Google Scholar

• 92

  DubuissonA.MicheauO. (2017). Antibodies and derivatives targeting DR4 and DR5 for cancer therapy. Antibodies (Basel)6 (4), 16. 10.3390/antib6040016

  • CrossRef
  • Google Scholar

• 93

  DuffyM. J.MurrayA.SynnottN. C.O'DonovanN.CrownJ. (2017). Vitamin D analogues: potential use in cancer treatment. Crit. Rev. Oncol. Hematol.112, 190–197. 10.1016/j.critrevonc.2017.02.015

  • CrossRef
  • Google Scholar

• 94

  DunkleA.HeY. W. (2011). Apoptosis and autophagy in the regulation of T lymphocyte function. Immunol. Res.49 (1-3), 70–86. 10.1007/s12026-010-8195-5

  • CrossRef
  • Google Scholar

• 95

  ElingN.ReuterL.HazinJ.Hamacher-BradyA.BradyN. R. (2015). Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience2 (5), 517–532. 10.18632/oncoscience.160

  • CrossRef
  • Google Scholar

• 96

  ElmoreS. (2007). Apoptosis: a review of programmed cell death. Toxicol. Pathol.35 (4), 495–516. 10.1080/01926230701320337

  • CrossRef
  • Google Scholar

• 97

  EmranT. B.ShahriarA.MahmudA. R.RahmanT.AbirM. H.SiddiqueeM. F.et al (2022). Multidrug resistance in cancer: understanding molecular mechanisms, immunoprevention and therapeutic approaches. Front. Oncol.12, 891652. 10.3389/fonc.2022.891652

  • CrossRef
  • Google Scholar

• 98

  ErkesD. A.CaiW.SanchezI. M.PurwinT. J.RogersC.FieldC. O.et al (2020). Mutant BRAF and MEK inhibitors regulate the tumor immune microenvironment via pyroptosis. Cancer Discov.10 (2), 254–269. 10.1158/2159-8290.CD-19-0672

  • CrossRef
  • Google Scholar

• 99

  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

  • CrossRef
  • Google Scholar

• 100

  FantoneS.PianiF.OlivieriF.RippoM. R.SiricoA.Di SimoneN.et al (2024). Role of slc7a11/xCT in ovarian cancer. Int. J. Mol. Sci.25 (1), 587. 10.3390/ijms25010587

  • CrossRef
  • Google Scholar

• 101

  FeldmannF.SchenkB.MartensS.VandenabeeleP.FuldaS. (2017). Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells. Oncotarget8 (40), 68208–68220. 10.18632/oncotarget.19919

  • CrossRef
  • Google Scholar

• 102

  FengS.FoxD.ManS. M. (2018). Mechanisms of gasdermin family members in inflammasome signaling and cell death. J. Mol. Biol.430 (18 Pt B), 3068–3080. 10.1016/j.jmb.2018.07.002

  • CrossRef
  • Google Scholar

• 103

  FengW.ShiW.LiuS.LiuH.LiuY.GeP.et al (2022). Fe(III)-Shikonin supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis. Adv. Healthc. Mater11 (2), e2101926. 10.1002/adhm.202101926

  • CrossRef
  • Google Scholar

• 104

  FengW.YeF.XueW.ZhouZ.KangY. J. (2009). Copper regulation of hypoxia-inducible factor-1 activity. Mol. Pharmacol.75 (1), 174–182. 10.1124/mol.108.051516

  • CrossRef
  • Google Scholar

• 105

  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

  • CrossRef
  • Google Scholar

• 106

  FengY.HeD.YaoZ.KlionskyD. J. (2014). The machinery of macroautophagy. Cell Res.24 (1), 24–41. 10.1038/cr.2013.168

  • CrossRef
  • Google Scholar

• 107

  FengY.YangZ.WangJ.ZhaoH. (2024). Cuproptosis: unveiling a new frontier in cancer biology and therapeutics. Cell Commun. Signal22 (1), 249. 10.1186/s12964-024-01625-7

  • CrossRef
  • Google Scholar

• 108

  FentonS. E.HussainM. (2024). Olaparib monotherapy or in combination with abiraterone for treating mutated metastatic castration-resistant prostate cancer: alone or stronger together?Expert Opin. Investig. Drugs33 (10), 993–999. 10.1080/13543784.2024.2391828

  • CrossRef
  • Google Scholar

• 109

  FizaziK.AzadA. A.MatsubaraN.CarlesJ.FayA. P.De GiorgiU.et al (2024). First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat. Med.30 (1), 257–264. 10.1038/s41591-023-02704-x

  • CrossRef
  • Google Scholar

• 110

  FongP. C.BossD. S.YapT. A.TuttA.WuP.Mergui-RoelvinkM.et al (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med.361 (2), 123–134. 10.1056/NEJMoa0900212

  • CrossRef
  • Google Scholar

• 111

  ForeroA.BendellJ. C.KumarP.JanischL.RosenM.WangQ.et al (2017). First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Invest. New Drugs35 (3), 298–306. 10.1007/s10637-016-0420-1

  • CrossRef
  • Google Scholar

• 112

  Forero-TorresA.InfanteJ. R.WaterhouseD.WongL.VickersS.ArrowsmithE.et al (2013). Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med.2 (6), 925–932. 10.1002/cam4.137

  • CrossRef
  • Google Scholar

• 113

  Forero-TorresA.ShahJ.WoodT.PoseyJ.CarlisleR.CopigneauxC.et al (2010). Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5). Cancer Biother Radiopharm.25 (1), 13–19. 10.1089/cbr.2009.0673

  • CrossRef
  • Google Scholar

• 114

  FranchiL.Munoz-PlanilloR.NunezG. (2012). Sensing and reacting to microbes through the inflammasomes. Nat. Immunol.13 (4), 325–332. 10.1038/ni.2231

  • CrossRef
  • Google Scholar

• 115

  FrenzelA.GrespiF.ChmelewskijW.VillungerA. (2009). Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis14 (4), 584–596. 10.1007/s10495-008-0300-z

  • CrossRef
  • Google Scholar

• 116

  FuldaS.VucicD. (2012). Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov.11 (2), 109–124. 10.1038/nrd3627

  • CrossRef
  • Google Scholar

• 117

  GaalA.GarayT. M.HorvathI.MatheD.SzollosiD.VeresD. S.et al (2020). Development and in vivo application of a water-soluble anticancer copper ionophore system using a temperature-sensitive liposome formulation. Pharmaceutics12 (5), 466. 10.3390/pharmaceutics12050466

  • CrossRef
  • Google Scholar

• 118

  GaliaA.CalogeroA. E.CondorelliR.FraggettaF.La CorteA.RidolfoF.et al (2012). PARP-1 protein expression in glioblastoma multiforme. Eur. J. Histochem56 (1), e9. 10.4081/ejh.2012.e9

  • CrossRef
  • Google Scholar

• 119

  GalluzziL.VitaleI.AaronsonS. A.AbramsJ. M.AdamD.AgostinisP.et al (2018). Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ.25 (3), 486–541. 10.1038/s41418-017-0012-4

  • CrossRef
  • Google Scholar

• 120

  GanL.WangJ.XuH.YangX. (2011). Resistance to docetaxel-induced apoptosis in prostate cancer cells by p38/p53/p21 signaling. Prostate71 (11), 1158–1166. 10.1002/pros.21331

  • CrossRef
  • Google Scholar

• 121

  GandhiL.CamidgeD. R.Ribeiro de OliveiraM.BonomiP.GandaraD.KhairaD.et al (2011). Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol.29 (7), 909–916. 10.1200/JCO.2010.31.6208

  • CrossRef
  • Google Scholar

• 122

  GaoW.HuangZ.DuanJ.NiceE. C.LinJ.HuangC. (2021). Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Mol. Oncol.15 (12), 3527–3544. 10.1002/1878-0261.13079

  • CrossRef
  • Google Scholar

• 123

  GardnerB. M.PincusD.GotthardtK.GallagherC. M.WalterP. (2013). Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol.5 (3), a013169. 10.1101/cshperspect.a013169

  • CrossRef
  • Google Scholar

• 124

  GaschlerM. M.AndiaA. A.LiuH.CsukaJ. M.HurlockerB.VaianaC. A.et al (2018). FINO(2) initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol.14 (5), 507–515. 10.1038/s41589-018-0031-6

  • CrossRef
  • Google Scholar

• 125

  GeE. J.BushA. I.CasiniA.CobineP. A.CrossJ. R.DeNicolaG. M.et al (2022). Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat. Rev. Cancer22 (2), 102–113. 10.1038/s41568-021-00417-2

  • CrossRef
  • Google Scholar

• 126

  GhasemiP.ShafieeG.ZiamajidiN.AbbasalipourkabirR. (2023). Copper nanoparticles induce apoptosis and oxidative stress in SW480 human colon cancer cell line. Biol. Trace Elem. Res.201 (8), 3746–3754. 10.1007/s12011-022-03458-2

  • CrossRef
  • Google Scholar

• 127

  GillH. (2024). Chemotherapy-free approaches to newly-diagnosed acute promyelocytic leukaemia: is oral-arsenic trioxide/all-trans retinoic acid/ascorbic acid the answer?Expert Rev. Hematol.17 (10), 661–667. 10.1080/17474086.2024.2391098

  • CrossRef
  • Google Scholar

• 128

  GillS.BrudnoJ. N. (2021). CAR T-cell therapy in hematologic malignancies: clinical role, toxicity, and unanswered questions. Am. Soc. Clin. Oncol. Educ. Book41, 1–20. 10.1200/EDBK_320085

  • CrossRef
  • Google Scholar

• 129

  GiordanoF.D'AmicoM.MontaltoF. I.MalivindiR.ChimentoA.ConfortiF. L.et al (2023). Cdk4 regulates glioblastoma cell invasion and stemness and is target of a notch inhibitor plus resveratrol combined treatment. Int. J. Mol. Sci.24 (12), 10094. 10.3390/ijms241210094

  • CrossRef
  • Google Scholar

• 130

  Gomez-VirgilioL.Silva-LuceroM. D.Flores-MorelosD. S.Gallardo-NietoJ.Lopez-ToledoG.Abarca-FernandezA. M.et al (2022). Autophagy: a key regulator of homeostasis and disease: an overview of molecular mechanisms and modulators. Cells11 (15), 2262. 10.3390/cells11152262

  • CrossRef
  • Google Scholar

• 131

  GongL.HuangD.ShiY.LiangZ.BuH. (2023). Regulated cell death in cancer: from pathogenesis to treatment. Chin. Med. J. Engl.136 (6), 653–665. 10.1097/CM9.0000000000002239

  • CrossRef
  • Google Scholar

• 132

  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

  • CrossRef
  • Google Scholar

• 133

  GordyC.HeY. W. (2012). The crosstalk between autophagy and apoptosis: where does this lead?Protein Cell3 (1), 17–27. 10.1007/s13238-011-1127-x

  • CrossRef
  • Google Scholar

• 134

  GoyA.Hernandez-IlzaliturriF. J.KahlB.FordP.ProtomastroE.BergerM. (2014). A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma. Leuk. Lymphoma55 (12), 2761–2768. 10.3109/10428194.2014.907891

  • CrossRef
  • Google Scholar

• 135

  GrecoF. A.BonomiP.CrawfordJ.KellyK.OhY.HalpernW.et al (2008). Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer61 (1), 82–90. 10.1016/j.lungcan.2007.12.011

  • CrossRef
  • Google Scholar

• 136

  GuL.ZhangH.LiuT.DraganovA.YiS.WangB.et al (2018). Inhibition of MDM2 by a rhein-derived compound AQ-101 suppresses cancer development in SCID mice. Mol. Cancer Ther.17 (2), 497–507. 10.1158/1535-7163.MCT-17-0566

  • CrossRef
  • Google Scholar

• 137

  GuoJ.XuB.HanQ.ZhouH.XiaY.GongC.et al (2018). Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res. Treat.50 (2), 445–460. 10.4143/crt.2016.572

  • CrossRef
  • Google Scholar

• 138

  HadianK.StockwellB. R. (2023). The therapeutic potential of targeting regulated non-apoptotic cell death. Nat. Rev. Drug Discov.22 (9), 723–742. 10.1038/s41573-023-00749-8

  • CrossRef
  • Google Scholar

• 139

  HalliwellB.ChiricoS. (1993). Lipid peroxidation: its mechanism, measurement, and significance. Am. J. Clin. Nutr.57 (5 Suppl. l), 715S–725S. 10.1093/ajcn/57.5.715S

  • CrossRef
  • Google Scholar

• 140

  HanQ.MaY.WangH.DaiY.ChenC.LiuY.et al (2018). Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis. J. Transl. Med.16 (1), 201. 10.1186/s12967-018-1580-x

  • CrossRef
  • Google Scholar

• 141

  HanW.LiL.QiuS.LuQ.PanQ.GuY.et al (2007). Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol. Cancer Ther.6 (5), 1641–1649. 10.1158/1535-7163.MCT-06-0511

  • CrossRef
  • Google Scholar

• 142

  HangauerM. J.ViswanathanV. S.RyanM. J.BoleD.EatonJ. K.MatovA.et al (2017). Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature551 (7679), 247–250. 10.1038/nature24297

  • CrossRef
  • Google Scholar

• 143

  HarrazM. M.DawsonT. M.DawsonV. L. (2008). Advances in neuronal cell death 2007. Stroke39 (2), 286–288. 10.1161/STROKEAHA.107.511857

  • CrossRef
  • Google Scholar

• 144

  HarshmanL. C.KroegerN.RhaS. Y.DonskovF.WoodL.TantravahiS. K.et al (2014). First-line Mammalian target of rapamycin inhibition in metastatic renal cell carcinoma: an analysis of practice patterns from the International Metastatic Renal Cell Carcinoma Database Consortium. Clin. Genitourin. Cancer12 (5), 335–340. 10.1016/j.clgc.2014.03.003

  • CrossRef
  • Google Scholar

• 145

  HeS.WangL.MiaoL.WangT.DuF.ZhaoL.et al (2009). Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell137 (6), 1100–1111. 10.1016/j.cell.2009.05.021

  • CrossRef
  • Google Scholar

• 146

  HeissB. L.ChangE.GaoX.TruongT.BraveM. H.BloomquistE.et al (2024). US food and drug administration approval summary: talazoparib in combination with enzalutamide for treatment of patients with homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer. J. Clin. Oncol.42 (15), 1851–1860. 10.1200/JCO.23.02182

  • CrossRef
  • Google Scholar

• 147

  HerbstR. S.KurzrockR.HongD. S.ValdiviesoM.HsuC. P.GoyalL.et al (2010). A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clin. Cancer Res.16 (23), 5883–5891. 10.1158/1078-0432.CCR-10-0631

  • CrossRef
  • Google Scholar

• 148

  Hergueta-RedondoM.SarrioD.Molina-CrespoA.VicarioR.Bernado-MoralesC.MartinezL.et al (2016). Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. Oncotarget7 (35), 56295–56308. 10.18632/oncotarget.10787

  • CrossRef
  • Google Scholar

• 149

  HitomiJ.ChristoffersonD. E.NgA.YaoJ.DegterevA.XavierR. J.et al (2008). Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell135 (7), 1311–1323. 10.1016/j.cell.2008.10.044

  • CrossRef
  • Google Scholar

• 150

  HotteS. J.HirteH. W.ChenE. X.SiuL. L.LeL. H.CoreyA.et al (2008). A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin. Cancer Res.14 (11), 3450–3455. 10.1158/1078-0432.CCR-07-1416

  • CrossRef
  • Google Scholar

• 151

  HuZ.CaiM.ZhangY.TaoL.GuoR. (2020). miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway. Cell Cycle19 (2), 193–206. 10.1080/15384101.2019.1704537

  • CrossRef
  • Google Scholar

• 152

  HuaL.ZhuG.WeiJ. (2018). MicroRNA-1 overexpression increases chemosensitivity of non-small cell lung cancer cells by inhibiting autophagy related 3-mediated autophagy. Cell Biol. Int.42 (9), 1240–1249. 10.1002/cbin.10995

  • CrossRef
  • Google Scholar

• 153

  HuaY.ZhengY.YaoY.JiaR.GeS.ZhuangA. (2023). Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J. Transl. Med.21 (1), 403. 10.1186/s12967-023-04263-8

  • CrossRef
  • Google Scholar

• 154

  HuangC. Y.YuL. C. (2015). Pathophysiological mechanisms of death resistance in colorectal carcinoma. World J. Gastroenterol.21 (41), 11777–11792. 10.3748/wjg.v21.i41.11777

  • CrossRef
  • Google Scholar

• 155

  HuangK. J.WeiY. H.ChiuY. C.WuS. R.ShiehD. B. (2019a). Assessment of zero-valent iron-based nanotherapeutics for ferroptosis induction and resensitization strategy in cancer cells. Biomater. Sci.7 (4), 1311–1322. 10.1039/c8bm01525b

  • CrossRef
  • Google Scholar

• 156

  HuangP.ChenG.JinW.MaoK.WanH.HeY. (2022). Molecular mechanisms of parthanatos and its role in diverse diseases. Int. J. Mol. Sci.23 (13), 7292. 10.3390/ijms23137292

  • CrossRef
  • Google Scholar

• 157

  HuangY. F.KuoM. T.LiuY. S.ChengY. M.WuP. Y.ChouC. Y. (2019b). A dose escalation study of trientine plus carboplatin and pegylated liposomal doxorubicin in women with a first relapse of epithelial ovarian, tubal, and peritoneal cancer within 12 Months after platinum-based chemotherapy. Front. Oncol.9, 437. 10.3389/fonc.2019.00437

  • CrossRef
  • Google Scholar

• 158

  HymowitzS. G.ChristingerH. W.FuhG.UltschM.O'ConnellM.KelleyR. F.et al (1999). Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol. Cell4 (4), 563–571. 10.1016/s1097-2765(00)80207-5

  • CrossRef
  • Google Scholar

• 159

  IshaqM.KhanM. A.SharmaK.SharmaG.DuttaR. K.MajumdarS. (2014). Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-κB, Beclin-1, p62 and NBR1) in human bladder cancer cells. Biochim. Biophys. Acta1840 (12), 3374–3384. 10.1016/j.bbagen.2014.08.019

  • CrossRef
  • Google Scholar

• 160

  IurlaroR.Munoz-PinedoC. (2016). Cell death induced by endoplasmic reticulum stress. FEBS J.283 (14), 2640–2652. 10.1111/febs.13598

  • CrossRef
  • Google Scholar

• 161

  JanR.ChaudhryG. E. (2019). Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv. Pharm. Bull.9 (2), 205–218. 10.15171/apb.2019.024

  • CrossRef
  • Google Scholar

• 162

  JeonS. M.ShinE. A. (2018). Exploring vitamin D metabolism and function in cancer. Exp. Mol. Med.50 (4), 20–14. 10.1038/s12276-018-0038-9

  • CrossRef
  • Google Scholar

• 163

  JiY.DaiF.ZhouB. (2018). Designing salicylaldehyde isonicotinoyl hydrazones as Cu(II) ionophores with tunable chelation and release of copper for hitting redox Achilles heel of cancer cells. Free Radic. Biol. Med.129, 215–226. 10.1016/j.freeradbiomed.2018.09.017

  • CrossRef
  • Google Scholar

• 164

  JiaY.WangX.DengY.LiS.XuX.QinY.et al (2023). Pyroptosis provides new strategies for the treatment of cancer. J. Cancer14 (1), 140–151. 10.7150/jca.77965

  • CrossRef
  • Google Scholar

• 165

  JiangY.ShenX.ZhiF.WenZ.GaoY.XuJ.et al (2023). An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications. Cell Death Discov.9 (1), 266. 10.1038/s41420-023-01558-z

  • CrossRef
  • Google Scholar

• 166

  JohnsonD. C.TaabazuingC. Y.OkondoM. C.ChuiA. J.RaoS. D.BrownF. C.et al (2018). DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat. Med.24 (8), 1151–1156. 10.1038/s41591-018-0082-y

  • CrossRef
  • Google Scholar

• 167

  JolyF.FabbroM.FollanaP.LequesneJ.MedioniJ.LesoinA.et al (2022). A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: the MONAVI - GINECO study. Gynecol. Oncol.165 (1), 30–39. 10.1016/j.ygyno.2022.01.021

  • CrossRef
  • Google Scholar

• 168

  KaczmarekA.VandenabeeleP.KryskoD. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity38 (2), 209–223. 10.1016/j.immuni.2013.02.003

  • CrossRef
  • Google Scholar

• 169

  KaganV. E.MaoG.QuF.AngeliJ. P.DollS.CroixC. S.et al (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol.13 (1), 81–90. 10.1038/nchembio.2238

  • CrossRef
  • Google Scholar

• 170

  KaiserW. J.SridharanH.HuangC.MandalP.UptonJ. W.GoughP. J.et al (2013). Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem.288 (43), 31268–31279. 10.1074/jbc.M113.462341

  • CrossRef
  • Google Scholar

• 171

  Kamgar-DayhoffP.BrelidzeT. I. (2021). Multifaceted effect of chlorpromazine in cancer: implications for cancer treatment. Oncotarget12 (14), 1406–1426. 10.18632/oncotarget.28010

  • CrossRef
  • Google Scholar

• 172

  KangZ.ChenJ. J.YuY.LiB.SunS. Y.ZhangB.et al (2011). Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response. Clin. Cancer Res.17 (10), 3181–3192. 10.1158/1078-0432.CCR-10-2874

  • CrossRef
  • Google Scholar

• 173

  KarkiR.KannegantiT. D. (2021). The 'cytokine storm': molecular mechanisms and therapeutic prospects. Trends Immunol.42 (8), 681–705. 10.1016/j.it.2021.06.001

  • CrossRef
  • Google Scholar

• 174

  KashbourM.AlhadeethiA.AwwadS.YassinM.AminA.AbedM.et al (2024). The efficacy of Veliparib in combination with chemotherapy in the treatment of lung cancer: systematic review and meta-analysis. Expert Rev. Anticancer Ther., 1–11. 10.1080/14737140.2024.2417770

  • CrossRef
  • Google Scholar

• 175

  KasofG. M.ProsserJ. C.LiuD.LorenziM. V.GomesB. C. (2000). The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. FEBS Lett.473 (3), 285–291. 10.1016/s0014-5793(00)01473-3

  • CrossRef
  • Google Scholar

• 176

  KasznickiJ.SliwinskaA.DrzewoskiJ. (2014). Metformin in cancer prevention and therapy. Ann. Transl. Med.2 (6), 57. 10.3978/j.issn.2305-5839.2014.06.01

  • CrossRef
  • Google Scholar

• 177

  KawamotoY.YamaiT.IkezawaK.SeikiY.WatsujiK.HiraoT.et al (2024). Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer. BMC Cancer24 (1), 1000. 10.1186/s12885-024-12722-8

  • CrossRef
  • Google Scholar

• 178

  KayagakiN.StoweI. B.LeeB. L.O'RourkeK.AndersonK.WarmingS.et al (2015). Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature526 (7575), 666–671. 10.1038/nature15541

  • CrossRef
  • Google Scholar

• 179

  KayagakiN.WebsterJ. D.NewtonK. (2024). Control of cell death in health and disease. Annu. Rev. Pathol.19, 157–180. 10.1146/annurev-pathmechdis-051022-014433

  • CrossRef
  • Google Scholar

• 180

  KeldsenN.HavsteenH.VergoteI.BertelsenK.JakobsenA. (2003). Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study. Gynecol. Oncol.88 (2), 118–122. 10.1016/s0090-8258(02)00103-8

  • CrossRef
  • Google Scholar

• 181

  KelleyK. C.GrossmanK. F.Brittain-BlankenshipM.ThorneK. M.AkerleyW. L.TerrazasM. C.et al (2021). A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker. BMC Cancer21 (1), 510. 10.1186/s12885-021-08242-4

  • CrossRef
  • Google Scholar

• 182

  KhanS. U.FatimaK.AishaS.MalikF. (2024). Unveiling the mechanisms and challenges of cancer drug resistance. Cell Commun. Signal22 (1), 109. 10.1186/s12964-023-01302-1

  • CrossRef
  • Google Scholar

• 183

  KimK. W.HwangM.MorettiL.JaboinJ. J.ChaY. I.LuB. (2008). Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy4 (5), 659–668. 10.4161/auto.6058

  • CrossRef
  • Google Scholar

• 184

  KimS. R.LewisJ. M.CyrenneB. M.MonicoP. F.MirzaF. N.CarlsonK. R.et al (2018). BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. Oncotarget9 (49), 29193–29207. 10.18632/oncotarget.25670

  • CrossRef
  • Google Scholar

• 185

  KindlerH. L.RichardsD. A.GarboL. E.GaronE. B.StephensonJ. J.Jr.Rocha-LimaC. M.et al (2012). A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann. Oncol.23 (11), 2834–2842. 10.1093/annonc/mds142

  • CrossRef
  • Google Scholar

• 186

  KochA.JeilerB.RoedigJ.van WijkS. J. L.DolgikhN.FuldaS. (2021). Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines. Neoplasia23 (5), 539–550. 10.1016/j.neo.2021.03.003

  • CrossRef
  • Google Scholar

• 187

  KonaS. V.KalivendiS. V. (2024). The USP10/13 inhibitor, spautin-1, attenuates the progression of glioblastoma by independently regulating RAF-ERK mediated glycolysis and SKP2. Biochim. Biophys. Acta Mol. Basis Dis.1870 (7), 167291. 10.1016/j.bbadis.2024.167291

  • CrossRef
  • Google Scholar

• 188

  KooG. B.MorganM. J.LeeD. G.KimW. J.YoonJ. H.KooJ. S.et al (2015). Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res.25 (6), 707–725. 10.1038/cr.2015.56

  • CrossRef
  • Google Scholar

• 189

  KorenE.FuchsY. (2021). Modes of regulated cell death in cancer. Cancer Discov.11 (2), 245–265. 10.1158/2159-8290.CD-20-0789

  • CrossRef
  • Google Scholar

• 190

  KouL.XieX.ChenX.LiB.LiJ.LiY. (2023). The progress of research on immune checkpoint inhibitor resistance and reversal strategies for hepatocellular carcinoma. Cancer Immunol. Immunother.72 (12), 3953–3969. 10.1007/s00262-023-03568-3

  • CrossRef
  • Google Scholar

• 191

  KrutilinaR. I.HartmanK. L.OluwalanaD.PlayaH. C.ParkeD. N.ChenH.et al (2022). Sabizabulin, a potent orally bioavailable colchicine binding site agent, suppresses HER2+ breast cancer and metastasis. Cancers (Basel)14 (21), 5336. 10.3390/cancers14215336

  • CrossRef
  • Google Scholar

• 192

  KuwaharaY.OikawaT.OchiaiY.RoudkenarM. H.FukumotoM.ShimuraT.et al (2011). Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy. Cell Death Dis.2 (6), e177. 10.1038/cddis.2011.56

  • CrossRef
  • Google Scholar

• 193

  LageH.HelmbachH.GrottkeC.DietelM.SchadendorfD. (2001). DFNA5 (ICERE-1) contributes to acquired etoposide resistance in melanoma cells. FEBS Lett.494 (1-2), 54–59. 10.1016/s0014-5793(01)02304-3

  • CrossRef
  • Google Scholar

• 194

  LamichhaneP. P.SamirP. (2023). Cellular stress: modulator of regulated cell death. Biol. (Basel)12 (9), 1172. 10.3390/biology12091172

  • CrossRef
  • Google Scholar

• 195

  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

  • CrossRef
  • Google Scholar

• 196

  LaraP. N.Jr.VillanuevaL.IbanezC.ErmanM.LeeJ. L.HeinrichD.et al (2024). A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302). BMC Cancer23 (Suppl. 1), 1253. 10.1186/s12885-023-10971-7

  • CrossRef
  • Google Scholar

• 197

  LeBlancH. N.AshkenaziA. (2003). Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ.10 (1), 66–75. 10.1038/sj.cdd.4401187

  • CrossRef
  • Google Scholar

• 198

  LeeH. O.MustafaA.HudesG. R.KrugerW. D. (2015). Hydroxychloroquine destabilizes phospho-S6 in human renal carcinoma cells. PLoS One10 (7), e0131464. 10.1371/journal.pone.0131464

  • CrossRef
  • Google Scholar

• 199

  LeeJ. M.BradyM. F.MillerA.MooreR. G.MacKayH.McNallyL.et al (2024). Cediranib and olaparib combination compared with cediranib or olaparib alone, or chemotherapy in platinum-resistant or primary platinum-refractory ovarian cancer: NRG-GY005. J. Clin. Oncol., JCO2400683. 10.1200/JCO.24.00683

  • CrossRef
  • Google Scholar

• 200

  LeeJ. M.KimH. S.KimA.ChangY. S.LeeJ. G.ChoJ.et al (2022). ABT-737, a BH3 mimetic, enhances the therapeutic effects of ionizing radiation in K-ras mutant non-small cell lung cancer preclinical model. Yonsei Med. J.63 (1), 16–25. 10.3349/ymj.2022.63.1.16

  • CrossRef
  • Google Scholar

• 201

  LeeS. Y.SeoJ. H.KimS.HwangC.JeongD. I.ParkJ.et al (2023). Cuproptosis-inducible chemotherapeutic/cascade catalytic reactor system for combating with breast cancer. Small19 (35), e2301402. 10.1002/smll.202301402

  • CrossRef
  • Google Scholar

• 202

  LehmannS.BykovV. J.AliD.AndrenO.CherifH.TidefeltU.et al (2012). Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol.30 (29), 3633–3639. 10.1200/JCO.2011.40.7783

  • CrossRef
  • Google Scholar

• 203

  LeiG.ZhangY.KoppulaP.LiuX.ZhangJ.LinS. H.et al (2020). The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res.30 (2), 146–162. 10.1038/s41422-019-0263-3

  • CrossRef
  • Google Scholar

• 204

  LeiG.ZhuangL.GanB. (2024). The roles of ferroptosis in cancer: tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell42 (4), 513–534. 10.1016/j.ccell.2024.03.011

  • CrossRef
  • Google Scholar

• 205

  LevantiniE. (2023). Novel therapeutic targets in cancers. Int. J. Mol. Sci.24 (19), 14660. 10.3390/ijms241914660

  • CrossRef
  • Google Scholar

• 206

  LevineA. J. (2022). Targeting the P53 protein for cancer therapies: the translational impact of P53 research. Cancer Res.82 (3), 362–364. 10.1158/0008-5472.CAN-21-2709

  • CrossRef
  • Google Scholar

• 207

  LiC.ZhangJ.PanP.ZhangJ.HouX.WangY.et al (2024a). Humanistic health management and cancer: associations of psychology, nutrition, and exercise with cancer progression and pathogenesis. Adv. Sci. (Weinh)11 (22), e2400665. 10.1002/advs.202400665

  • CrossRef
  • Google Scholar

• 208

  LiH.LiuW.ZhangX.WuF.SunD.WangZ. (2021). Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis. Biochem. Biophys. Res. Commun.585, 111–116. 10.1016/j.bbrc.2021.11.029

  • CrossRef
  • Google Scholar

• 209

  LiJ.ChenS.LiaoY.WangH.ZhouD.ZhangB. (2022a). Arecoline is associated with inhibition of cuproptosis and proliferation of cancer-associated fibroblasts in oral squamous cell carcinoma: a potential mechanism for tumor metastasis. Front. Oncol.12, 925743. 10.3389/fonc.2022.925743

  • CrossRef
  • Google Scholar

• 210

  LiK.TanL.LiY.LyuY.ZhengX.JiangH.et al (2022b). Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis. Apoptosis27 (11-12), 1004–1014. 10.1007/s10495-022-01769-2

  • CrossRef
  • Google Scholar

• 211

  LiL. G.PengX. C.YangZ. Y.HanN.GouC. L.ShiJ.et al (2024b). Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage. Sci. Rep.14 (1), 11704. 10.1038/s41598-024-62126-8

  • CrossRef
  • Google Scholar

• 212

  LiQ.LvD.SunX.WangM.CaiL.LiuF.et al (2024c). Inetetamab combined with sirolimus and chemotherapy for the treatment of HER2-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR pathway after trastuzumab treatment. Cancer Innov.3 (5), e145. 10.1002/cai2.145

  • CrossRef
  • Google Scholar

• 213

  LiR.DingC.ZhangJ.XieM.ParkD.DingY.et al (2017). Modulation of Bax and mTOR for cancer therapeutics. Cancer Res.77 (11), 3001–3012. 10.1158/0008-5472.CAN-16-2356

  • CrossRef
  • Google Scholar

• 214

  LiX.ZhouY.LiY.YangL.MaY.PengX.et al (2019). Autophagy: a novel mechanism of chemoresistance in cancers. Biomed. Pharmacother.119, 109415. 10.1016/j.biopha.2019.109415

  • CrossRef
  • Google Scholar

• 215

  LiaoM.QinR.HuangW.ZhuH. P.PengF.HanB.et al (2022a). Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies. J. Hematol. Oncol.15 (1), 44. 10.1186/s13045-022-01260-0

  • CrossRef
  • Google Scholar

• 216

  LiaoP.WangW.WangW.KryczekI.LiX.BianY.et al (2022b). CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell40 (4), 365–378.e6. 10.1016/j.ccell.2022.02.003

  • CrossRef
  • Google Scholar

• 217

  LinS. Q.JiaF. J.ZhangC. Y.LiuF. Y.MaJ. H.HanZ.et al (2019a). Actinomycin V suppresses human non-small-cell lung carcinoma A549 cells by inducing G2/M phase arrest and apoptosis via the p53-dependent pathway. Mar. Drugs17 (10), 572. 10.3390/md17100572

  • CrossRef
  • Google Scholar

• 218

  LinX.JiaY.DongX.ShenJ.JinY.LiY.et al (2019b). Diplatin, a novel and low-toxicity anti-lung cancer platinum complex, activation of cell death in tumors via a ROS/JNK/p53-Dependent pathway, and a low rate of acquired treatment resistance. Front. Pharmacol.10, 982. 10.3389/fphar.2019.00982

  • CrossRef
  • Google Scholar

• 219

  LindemannA.PatelA. A.SilverN. L.TangL.LiuZ.WangL.et al (2019). COTI-2, A novel thiosemicarbazone derivative, exhibits antitumor activity in HNSCC through p53-dependent and -independent mechanisms. Clin. Cancer Res.25 (18), 5650–5662. 10.1158/1078-0432.CCR-19-0096

  • CrossRef
  • Google Scholar

• 220

  LiuB.ZhouH.TanL.SiuK. T. H.GuanX. Y. (2024a). Exploring treatment options in cancer: tumor treatment strategies. Signal Transduct. Target Ther.9 (1), 175. 10.1038/s41392-024-01856-7

  • CrossRef
  • Google Scholar

• 221

  LiuJ.KuangF.KroemerG.KlionskyD. J.KangR.TangD. (2020a). Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem. Biol.27 (4), 420–435. 10.1016/j.chembiol.2020.02.005

  • CrossRef
  • Google Scholar

• 222

  LiuJ.YuanY.ChengY.FuD.ChenZ.WangY.et al (2022). Copper-based metal-organic framework overcomes cancer chemoresistance through systemically disrupting dynamically balanced cellular redox homeostasis. J. Am. Chem. Soc.144 (11), 4799–4809. 10.1021/jacs.1c11856

  • CrossRef
  • Google Scholar

• 223

  LiuS.YaoS.YangH.LiuS.WangY. (2023). Autophagy: regulator of cell death. Cell Death Dis.14 (10), 648. 10.1038/s41419-023-06154-8

  • CrossRef
  • Google Scholar

• 224

  LiuT.SunX.CaoZ. (2019). Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression. Onco Targets Ther.12, 2605–2614. 10.2147/OTT.S200740

  • CrossRef
  • Google Scholar

• 225

  LiuX.ZhouM.MeiL.RuanJ.HuQ.PengJ.et al (2016). Key roles of necroptotic factors in promoting tumor growth. Oncotarget7 (16), 22219–22233. 10.18632/oncotarget.7924

  • CrossRef
  • Google Scholar

• 226

  LiuY.FangY.ChenX.WangZ.LiangX.ZhangT.et al (2020b). Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci. Immunol.5 (43), eaax7969. 10.1126/sciimmunol.aax7969

  • CrossRef
  • Google Scholar

• 227

  LiuY.MondelloP.ErazoT.TannanN. B.AsgariZ.de StanchinaE.et al (2018). NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proc. Natl. Acad. Sci. U. S. A.115 (47), 12034–12039. 10.1073/pnas.1806928115

  • CrossRef
  • Google Scholar

• 228

  LiuY.PanR.OuyangY.GuW.XiaoT.YangH.et al (2024b). Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. Signal Transduct. Target Ther.9 (1), 245. 10.1038/s41392-024-01958-2

  • CrossRef
  • Google Scholar

• 229

  LiuZ. Y.WuB.GuoY. S.ZhouY. H.FuZ. G.XuB. Q.et al (2015). Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice. Am. J. Cancer Res.5 (10), 3174–3185.

  • Google Scholar

• 230

  LlovetJ. M.RicciS.MazzaferroV.HilgardP.GaneE.BlancJ. F.et al (2008). Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med.359 (4), 378–390. 10.1056/NEJMoa0708857

  • CrossRef
  • Google Scholar

• 231

  LoiS.KarapetisC. S.McCarthyN.OakmanC.RedfernA.WhiteM.et al (2022). Palbociclib plus letrozole as treatment for postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate: an expanded access study in Australia and India. Asia Pac J. Clin. Oncol.18 (6), 560–569. 10.1111/ajco.13653

  • CrossRef
  • Google Scholar

• 232

  LoweS. W.LinA. W. (2000). Apoptosis in cancer. Carcinogenesis21 (3), 485–495. 10.1093/carcin/21.3.485

  • CrossRef
  • Google Scholar

• 233

  LuW.ChengF.YanW.LiX.YaoX.SongW.et al (2017). Selective targeting p53(WT) lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA. Oncogene36 (33), 4719–4731. 10.1038/onc.2017.41

  • CrossRef
  • Google Scholar

• 234

  LuX.ChenL.ChenY.ShaoQ.QinW. (2015). Bafilomycin A1 inhibits the growth and metastatic potential of the BEL-7402 liver cancer and HO-8910 ovarian cancer cell lines and induces alterations in their microRNA expression. Exp. Ther. Med.10 (5), 1829–1834. 10.3892/etm.2015.2758

  • CrossRef
  • Google Scholar

• 235

  LuZ.WuC.ZhuM.SongW.WangH.WangJ.et al (2020). Ophiopogonin D' induces RIPK1-dependent necroptosis in androgen-dependent LNCaP prostate cancer cells. Int. J. Oncol.56 (2), 439–447. 10.3892/ijo.2019.4945

  • CrossRef
  • Google Scholar

• 236

  LuoY.BaiX. Y.ZhangL.HuQ. Q.ZhangN.ChengJ. Z.et al (2024). Ferroptosis in cancer therapy: mechanisms, small molecule inducers, and novel approaches. Drug Des. Devel Ther.18, 2485–2529. 10.2147/DDDT.S472178

  • CrossRef
  • Google Scholar

• 237

  MaD.LuB.FengC.WangC.WangY.LuoT.et al (2016a). Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS. Cancer Lett.371 (2), 194–204. 10.1016/j.canlet.2015.11.044

  • CrossRef
  • Google Scholar

• 238

  MaJ.LiL.YueK.LiY.LiuH.WangP. G.et al (2020). Bromocoumarinplatin, targeting simultaneously mitochondria and nuclei with p53 apoptosis pathway to overcome cisplatin resistance. Bioorg Chem.99, 103768. 10.1016/j.bioorg.2020.103768

  • CrossRef
  • Google Scholar

• 239

  MaS.HensonE. S.ChenY.GibsonS. B. (2016b). Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis.7 (7), e2307. 10.1038/cddis.2016.208

  • CrossRef
  • Google Scholar

• 240

  MaS.ZhuJ.WangM.ZhuJ.WangW.XiongY.et al (2022). A cuproptosis-related long non-coding RNA signature to predict the prognosis and immune microenvironment characterization for lung adenocarcinoma. Transl. Lung Cancer Res.11 (10), 2079–2093. 10.21037/tlcr-22-660

  • CrossRef
  • Google Scholar

• 241

  MaX.XiaoL.LiuL.YeL.SuP.BiE.et al (2021). CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab.33 (5), 1001–1012.e5. 10.1016/j.cmet.2021.02.015

  • CrossRef
  • Google Scholar

• 242

  MaZ. G.MaR.XiaoX. L.ZhangY. H.ZhangX. Z.HuN.et al (2016c). Azo polymeric micelles designed for colon-targeted dimethyl fumarate delivery for colon cancer therapy. Acta Biomater.44, 323–331. 10.1016/j.actbio.2016.08.021

  • CrossRef
  • Google Scholar

• 243

  MacDonaldG.NalvarteI.SmirnovaT.VecchiM.AcetoN.DolemeyerA.et al (2014). Memo is a copper-dependent redox protein with an essential role in migration and metastasis. Sci. Signal7 (329), ra56. 10.1126/scisignal.2004870

  • CrossRef
  • Google Scholar

• 244

  MahalingamD.MitaM.SarantopoulosJ.WoodL.AmaravadiR. K.DavisL. E.et al (2014). Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy10 (8), 1403–1414. 10.4161/auto.29231

  • CrossRef
  • Google Scholar

• 245

  Maleki VarekiS.SalimK. Y.DanterW. R.KoropatnickJ. (2018). Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines. PLoS One13 (1), e0191766. 10.1371/journal.pone.0191766

  • CrossRef
  • Google Scholar

• 246

  ManS. M.KarkiR.KannegantiT. D. (2017). Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev.277 (1), 61–75. 10.1111/imr.12534

  • CrossRef
  • Google Scholar

• 247

  MannB. S.JohnsonJ. R.CohenM. H.JusticeR.PazdurR. (2007). FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist12 (10), 1247–1252. 10.1634/theoncologist.12-10-1247

  • CrossRef
  • Google Scholar

• 248

  MarkowskiM. C.TutroneR.PieczonkaC.BarnetteK. G.GetzenbergR. H.RodriguezD.et al (2022). A phase ib/II study of sabizabulin, a novel oral cytoskeleton disruptor, in men with metastatic castration-resistant prostate cancer with progression on an androgen receptor-targeting agent. Clin. Cancer Res.28 (13), 2789–2795. 10.1158/1078-0432.CCR-22-0162

  • CrossRef
  • Google Scholar

• 249

  MarshJ. W.DjokoK. Y.McEwanA. G.HustonW. M. (2017). Copper(II)-bis(thiosemicarbazonato) complexes as anti-chlamydial agents. Pathog. Dis.75 (7). 10.1093/femspd/ftx084

  • CrossRef
  • Google Scholar

• 250

  MaruD.HothiA.BagariyaC.KumarA. (2022). Targeting ferroptosis pathways: a novel strategy for cancer therapy. Curr. Cancer Drug Targets22 (3), 234–244. 10.2174/1568009622666220211122745

  • CrossRef
  • Google Scholar

• 251

  MasaldanS.ClatworthyS. A. S.GamellC.MeggyesyP. M.RigopoulosA. T.HauptS.et al (2018). Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol.14, 100–115. 10.1016/j.redox.2017.08.015

  • CrossRef
  • Google Scholar

• 252

  MasonK. A.ValdecanasD.HunterN. R.MilasL. (2008). INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin. Invest. New Drugs26 (1), 1–5. 10.1007/s10637-007-9072-5

  • CrossRef
  • Google Scholar

• 253

  MateoJ.MorenoV.GuptaA.KayeS. B.DeanE.MiddletonM. R.et al (2016). An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target Oncol.11 (3), 401–415. 10.1007/s11523-016-0435-8

  • CrossRef
  • Google Scholar

• 254

  MatteoniS.MatarreseP.AscioneB.BuccarelliM.Ricci-VitianiL.PalliniR.et al (2021). Anticancer properties of the antipsychotic drug chlorpromazine and its synergism with temozolomide in restraining human glioblastoma proliferation in vitro. Front. Oncol.11, 635472. 10.3389/fonc.2021.635472

  • CrossRef
  • Google Scholar

• 255

  McIlwainD. R.BergerT.MakT. W. (2015). Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol.7 (4), a026716. 10.1101/cshperspect.a026716

  • CrossRef
  • Google Scholar

• 256

  MeierP.LegrandA. J.AdamD.SilkeJ. (2024). Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nat. Rev. Cancer24 (5), 299–315. 10.1038/s41568-024-00674-x

  • CrossRef
  • Google Scholar

• 257

  MeleL.Del VecchioV.LiccardoD.PriscoC.SchwerdtfegerM.RobinsonN.et al (2020). The role of autophagy in resistance to targeted therapies. Cancer Treat. Rev.88, 102043. 10.1016/j.ctrv.2020.102043

  • CrossRef
  • Google Scholar

• 258

  MengM. B.WangH. H.CuiY. L.WuZ. Q.ShiY. Y.ZaorskyN. G.et al (2016). Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy. Oncotarget7 (35), 57391–57413. 10.18632/oncotarget.10548

  • CrossRef
  • Google Scholar

• 259

  MichieJ.KearneyC. J.HawkinsE. D.SilkeJ.OliaroJ. (2020). The immuno-modulatory effects of inhibitor of apoptosis protein antagonists in cancer immunotherapy. Cells9 (1), 207. 10.3390/cells9010207

  • CrossRef
  • Google Scholar

• 260

  MishraR.Zokaei NikooM.VeeraballiS.SinghA. (2023). Venetoclax and hypomethylating agent combination in myeloid malignancies: mechanisms of synergy and challenges of resistance. Int. J. Mol. Sci.25 (1), 484. 10.3390/ijms25010484

  • CrossRef
  • Google Scholar

• 261

  MizunoM.ItoK.NakaiH.KatoH.KamiuraS.UshijimaK.et al (2023). Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial. Int. J. Clin. Oncol.28 (1), 163–174. 10.1007/s10147-022-02258-x

  • CrossRef
  • Google Scholar

• 262

  MohammadR. M.MuqbilI.LoweL.YedjouC.HsuH. Y.LinL. T.et al (2015). Broad targeting of resistance to apoptosis in cancer. Semin. Cancer Biol.35, S78–S103. 10.1016/j.semcancer.2015.03.001

  • CrossRef
  • Google Scholar

• 263

  MohammadinejadR.MoosaviM. A.TavakolS.VardarD. O.HosseiniA.RahmatiM.et al (2019). Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles. Autophagy15 (1), 4–33. 10.1080/15548627.2018.1509171

  • CrossRef
  • Google Scholar

• 264

  Molina-CrespoA.CadeteA.SarrioD.Gamez-ChiachioM.MartinezL.ChaoK.et al (2019). Intracellular delivery of an antibody targeting gasdermin-B reduces HER2 breast cancer aggressiveness. Clin. Cancer Res.25 (15), 4846–4858. 10.1158/1078-0432.CCR-18-2381

  • CrossRef
  • Google Scholar

• 265

  MonianP.JiangX. (2012). Clearing the final hurdles to mitochondrial apoptosis: regulation post cytochrome C release. Exp. Oncol.34 (3), 185–191.

  • Google Scholar

• 266

  MonkB. J.ParkinsonC.LimM. C.O'MalleyD. M.OakninA.WilsonM. K.et al (2022). A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J. Clin. Oncol.40 (34), 3952–3964. 10.1200/JCO.22.01003

  • CrossRef
  • Google Scholar

• 267

  MoranaO.WoodW.GregoryC. D. (2022). The apoptosis paradox in cancer. Int. J. Mol. Sci.23 (3), 1328. 10.3390/ijms23031328

  • CrossRef
  • Google Scholar

• 268

  MorganM. J.KimY. S. (2022). Roles of RIPK3 in necroptosis, cell signaling, and disease. Exp. Mol. Med.54 (10), 1695–1704. 10.1038/s12276-022-00868-z

  • CrossRef
  • Google Scholar

• 269

  MotzerR. J.EscudierB.OudardS.HutsonT. E.PortaC.BracardaS.et al (2008). Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet372 (9637), 449–456. 10.1016/S0140-6736(08)61039-9

  • CrossRef
  • Google Scholar

• 270

  MurphyJ. M. (2020). The killer pseudokinase mixed lineage kinase domain-like protein (MLKL). Cold Spring Harb. Perspect. Biol.12 (8), a036376. 10.1101/cshperspect.a036376

  • CrossRef
  • Google Scholar

• 271

  NagaiM.VoN. H.Shin OgawaL.ChimmanamadaD.InoueT.ChuJ.et al (2012). The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radic. Biol. Med.52 (10), 2142–2150. 10.1016/j.freeradbiomed.2012.03.017

  • CrossRef
  • Google Scholar

• 272

  NagourneyA. J.GipoorJ. B.EvansS. S.D'AmoraP.DuesbergM. S.BernardP. J.et al (2023). Therapeutic targeting of P53: a comparative analysis of APR-246 and COTI-2 in human tumor primary culture 3-D explants. Genes (Basel)14 (3), 747. 10.3390/genes14030747

  • CrossRef
  • Google Scholar

• 273

  NajafovA.ChenH.YuanJ. (2017). Necroptosis and cancer. Trends Cancer3 (4), 294–301. 10.1016/j.trecan.2017.03.002

  • CrossRef
  • Google Scholar

• 274

  NarangA.Hage ChehadeC.OzayZ. I.NordbladB.SwamiU.AgarwalN. (2024). Talazoparib for the treatment of prostate cancer. Expert Opin. Pharmacother.25 (13), 1717–1727. 10.1080/14656566.2024.2397002

  • CrossRef
  • Google Scholar

• 275

  NawrockiS. T.HanY.VisconteV.PrzychodzenB.EspitiaC. M.PhillipsJ.et al (2019). The novel autophagy inhibitor ROC-325 augments the antileukemic activity of azacitidine. Leukemia33 (12), 2971–2974. 10.1038/s41375-019-0529-2

  • CrossRef
  • Google Scholar

• 276

  NawrockiS. T.WangW.CarewJ. S. (2020). Autophagy: new insights into its roles in cancer progression and drug resistance. Cancers (Basel)12 (10), 3005. 10.3390/cancers12103005

  • CrossRef
  • Google Scholar

• 277

  NegroniA.ColantoniE.CucchiaraS.StronatiL. (2020). Necroptosis in intestinal inflammation and cancer: new concepts and therapeutic perspectives. Biomolecules10 (10), 1431. 10.3390/biom10101431

  • CrossRef
  • Google Scholar

• 278

  NewtonK.DuggerD. L.WickliffeK. E.KapoorN.de AlmagroM. C.VucicD.et al (2014). Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science343 (6177), 1357–1360. 10.1126/science.1249361

  • CrossRef
  • Google Scholar

• 279

  NewtonK.StrasserA.KayagakiN.DixitV. M. (2024). Cell death. Cell187 (2), 235–256. 10.1016/j.cell.2023.11.044

  • CrossRef
  • Google Scholar

• 280

  NieZ.ChenM.GaoY.HuangD.CaoH.PengY.et al (2022). Ferroptosis and tumor drug resistance: current status and major challenges. Front. Pharmacol.13, 879317. 10.3389/fphar.2022.879317

  • CrossRef
  • Google Scholar

• 281

  NishikawaT.MatsumotoK.TamuraK.YoshidaH.ImaiY.MiyasakaA.et al (2017). Phase 1 dose-escalation study of single-agent veliparib in Japanese patients with advanced solid tumors. Cancer Sci.108 (9), 1834–1842. 10.1111/cas.13307

  • CrossRef
  • Google Scholar

• 282

  Nor HisamN. S.UgusmanA.RajabN. F.AhmadM. F.FenechM.LiewS. L.et al (2021). Combination therapy of navitoclax with chemotherapeutic agents in solid tumors and blood cancer: a review of current evidence. Pharmaceutics13 (9), 1353. 10.3390/pharmaceutics13091353

  • CrossRef
  • Google Scholar

• 283

  O'DayS. J.EggermontA. M.Chiarion-SileniV.KeffordR.GrobJ. J.MortierL.et al (2013). Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J. Clin. Oncol.31 (9), 1211–1218. 10.1200/JCO.2012.44.5585

  • CrossRef
  • Google Scholar

• 284

  OjhaR.JhaV.SinghS. K. (2016). Gemcitabine and mitomycin induced autophagy regulates cancer stem cell pool in urothelial carcinoma cells. Biochim. Biophys. Acta1863 (2), 347–359. 10.1016/j.bbamcr.2015.12.002

  • CrossRef
  • Google Scholar

• 285

  OliveriV. (2022). Selective targeting of cancer cells by copper ionophores: an overview. Front. Mol. Biosci.9, 841814. 10.3389/fmolb.2022.841814

  • CrossRef
  • Google Scholar

• 286

  OliveriV.LanzaV.MilardiD.VialeM.MaricI.SgarlataC.et al (2017). Amino- and chloro-8-hydroxyquinolines and their copper complexes as proteasome inhibitors and antiproliferative agents. Metallomics9 (10), 1439–1446. 10.1039/c7mt00156h

  • CrossRef
  • Google Scholar

• 287

  Ozyerli-GoknarE.Bagci-OnderT. (2021). Epigenetic deregulation of apoptosis in cancers. Cancers (Basel)13 (13), 3210. 10.3390/cancers13133210

  • CrossRef
  • Google Scholar

• 288

  PaikP. K.RudinC. M.PietanzaM. C.BrownA.RizviN. A.TakebeN.et al (2011). A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer74 (3), 481–485. 10.1016/j.lungcan.2011.05.005

  • CrossRef
  • Google Scholar

• 289

  ParikhS. A.KantarjianH.SchimmerA.WalshW.AsatianiE.El-ShamiK.et al (2010). Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin. Lymphoma Myeloma Leuk.10 (4), 285–289. 10.3816/CLML.2010.n.059

  • CrossRef
  • Google Scholar

• 290

  ParkE. J.MinK. J.LeeT. J.YooY. H.KimY. S.KwonT. K. (2014). β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells. Cell Death Dis.5 (5), e1230. 10.1038/cddis.2014.202

  • CrossRef
  • Google Scholar

• 291

  ParkJ. M.HuangS.WuT. T.FosterN. R.SinicropeF. A. (2013). Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy. Cancer Biol. Ther.14 (2), 100–107. 10.4161/cbt.22954

  • CrossRef
  • Google Scholar

• 292

  ParzychK. R.KlionskyD. J. (2014). An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal20 (3), 460–473. 10.1089/ars.2013.5371

  • CrossRef
  • Google Scholar

• 293

  PasparakisM.VandenabeeleP. (2015). Necroptosis and its role in inflammation. Nature517 (7534), 311–320. 10.1038/nature14191

  • CrossRef
  • Google Scholar

• 294

  PasquierB. (2015). SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy11 (4), 725–726. 10.1080/15548627.2015.1033601

  • CrossRef
  • Google Scholar

• 295

  PazzagliaS.PioliC. (2019). Multifaceted role of PARP-1 in DNA repair and inflammation: pathological and therapeutic implications in cancer and non-cancer diseases. Cells9 (1), 41. 10.3390/cells9010041

  • CrossRef
  • Google Scholar

• 296

  PellegriniP.StrambiA.ZipoliC.Hagg-OlofssonM.BuoncervelloM.LinderS.et al (2014). Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. Autophagy10 (4), 562–571. 10.4161/auto.27901

  • CrossRef
  • Google Scholar

• 297

  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

  • CrossRef
  • Google Scholar

• 298

  PetsriK.ChamniS.SuwanboriruxK.SaitoN.ChanvorachoteP. (2019). Renieramycin T induces lung cancer cell apoptosis by targeting mcl-1 degradation: a new insight in the mechanism of action. Mar. Drugs17 (5), 301. 10.3390/md17050301

  • CrossRef
  • Google Scholar

• 299

  PfefferC. M.SinghA. T. K. (2018). Apoptosis: a target for anticancer therapy. Int. J. Mol. Sci.19 (2), 448. 10.3390/ijms19020448

  • CrossRef
  • Google Scholar

• 300

  PiccoloM.FerraroM. G.IazzettiF.SantamariaR.IraceC. (2024). Insight into iron, oxidative stress and ferroptosis: therapy targets for approaching anticancer strategies. Cancers (Basel)16 (6), 1220. 10.3390/cancers16061220

  • CrossRef
  • Google Scholar

• 301

  Piha-PaulS. A.TsengC.LeungC. H.YuanY.KarpD. D.SubbiahV.et al (2024). Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations. NPJ Precis. Oncol.8 (1), 166. 10.1038/s41698-024-00634-6

  • CrossRef
  • Google Scholar

• 302

  PizatoN.LuzeteB. C.KifferL.CorreaL. H.de Oliveira SantosI.AssumpcaoJ. A. F.et al (2018). Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells. Sci. Rep.8 (1), 1952. 10.1038/s41598-018-20422-0

  • CrossRef
  • Google Scholar

• 303

  PuF.ChenF.ZhangZ.ShiD.ZhongB.LvX.et al (2022). Ferroptosis as a novel form of regulated cell death: implications in the pathogenesis, oncometabolism and treatment of human cancer. Genes Dis.9 (2), 347–357. 10.1016/j.gendis.2020.11.019

  • CrossRef
  • Google Scholar

• 304

  PukacL.KanakarajP.HumphreysR.AldersonR.BloomM.SungC.et al (2005). HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br. J. Cancer92 (8), 1430–1441. 10.1038/sj.bjc.6602487

  • CrossRef
  • Google Scholar

• 305

  QiD.PengM. (2023). Ferroptosis-mediated immune responses in cancer. Front. Immunol.14, 1188365. 10.3389/fimmu.2023.1188365

  • CrossRef
  • Google Scholar

• 306

  QinK.ZhangF.WangH.WangN.QiuH.JiaX.et al (2023). circRNA circSnx12 confers Cisplatin chemoresistance to ovarian cancer by inhibiting ferroptosis through a miR-194-5p/SLC7A11 axis. BMB Rep.56 (2), 184–189. 10.5483/BMBRep.2022-0175

  • CrossRef
  • Google Scholar

• 307

  RangwalaR.ChangY. C.HuJ.AlgazyK. M.EvansT. L.FecherL. A.et al (2014a). Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy10 (8), 1391–1402. 10.4161/auto.29119

  • CrossRef
  • Google Scholar

• 308

  RangwalaR.LeoneR.ChangY. C.FecherL. A.SchuchterL. M.KramerA.et al (2014b). Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy10 (8), 1369–1379. 10.4161/auto.29118

  • CrossRef
  • Google Scholar

• 309

  RaoZ.ZhuY.YangP.ChenZ.XiaY.QiaoC.et al (2022). Pyroptosis in inflammatory diseases and cancer. Theranostics12 (9), 4310–4329. 10.7150/thno.71086

  • CrossRef
  • Google Scholar

• 310

  RashmiK. C.Harsha RajM.PaulM.GirishK. S.SalimathB. P.AparnaH. S. (2019). A new pyrrole based small molecule from Tinospora cordifolia induces apoptosis in MDA-MB-231 breast cancer cells via ROS mediated mitochondrial damage and restoration of p53 activity. Chem. Biol. Interact.299, 120–130. 10.1016/j.cbi.2018.12.005

  • CrossRef
  • Google Scholar

• 311

  RebeccaV. W.NicastriM. C.FennellyC.ChudeC. I.Barber-RotenbergJ. S.RongheA.et al (2019). PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov.9 (2), 220–229. 10.1158/2159-8290.CD-18-0706

  • CrossRef
  • Google Scholar

• 312

  RebeccaV. W.NicastriM. C.McLaughlinN.FennellyC.McAfeeQ.RongheA.et al (2017). A unified approach to targeting the lysosome's degradative and growth signaling roles. Cancer Discov.7 (11), 1266–1283. 10.1158/2159-8290.CD-17-0741

  • CrossRef
  • Google Scholar

• 313

  ReckM.SchenkerM.LeeK. H.ProvencioM.NishioM.Lesniewski-KmakK.et al (2019). Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur. J. Cancer116, 137–147. 10.1016/j.ejca.2019.05.008

  • CrossRef
  • Google Scholar

• 314

  RedmanB. G.EsperP.PanQ.DunnR. L.HussainH. K.ChenevertT.et al (2003). Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin. Cancer Res.9 (5), 1666–1672.

  • Google Scholar

• 315

  ReedJ. C. (2006). Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat. Clin. Pract. Oncol.3 (7), 388–398. 10.1038/ncponc0538

  • CrossRef
  • Google Scholar

• 316

  ReederN. L.KaplanJ.XuJ.YoungquistR. S.WallaceJ.HuP.et al (2011). Zinc pyrithione inhibits yeast growth through copper influx and inactivation of iron-sulfur proteins. Antimicrob. Agents Chemother.55 (12), 5753–5760. 10.1128/AAC.00724-11

  • CrossRef
  • Google Scholar

• 317

  Rocha LimaC. M.BayraktarS.FloresA. M.MacIntyreJ.MonteroA.BarandaJ. C.et al (2012). Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. Cancer Invest.30 (10), 727–731. 10.3109/07357907.2012.732163

  • CrossRef
  • Google Scholar

• 318

  RodlerE.SharmaP.BarlowW. E.GralowJ. R.PuhallaS. L.AndersC. K.et al (2023). Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol.24 (2), 162–174. 10.1016/S1470-2045(22)00739-2

  • CrossRef
  • Google Scholar

• 319

  RogersC.ErkesD. A.NardoneA.AplinA. E.Fernandes-AlnemriT.AlnemriE. S. (2019). Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun.10 (1), 1689. 10.1038/s41467-019-09397-2

  • CrossRef
  • Google Scholar

• 320

  RohJ. L.KimE. H.JangH. J.ParkJ. Y.ShinD. (2016). Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett.381 (1), 96–103. 10.1016/j.canlet.2016.07.035

  • CrossRef
  • Google Scholar

• 321

  RosenfeldM. R.YeX.SupkoJ. G.DesideriS.GrossmanS. A.BremS.et al (2014). A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy10 (8), 1359–1368. 10.4161/auto.28984

  • CrossRef
  • Google Scholar

• 322

  RudinC. M.HannC. L.GaronE. B.Ribeiro de OliveiraM.BonomiP. D.CamidgeD. R.et al (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res.18 (11), 3163–3169. 10.1158/1078-0432.CCR-11-3090

  • CrossRef
  • Google Scholar

• 323

  RuizL. M.LibedinskyA.ElorzaA. A. (2021). Role of copper on mitochondrial function and metabolism. Front. Mol. Biosci.8, 711227. 10.3389/fmolb.2021.711227

  • CrossRef
  • Google Scholar

• 324

  RussoA. L.KwonH. C.BurganW. E.CarterD.BeamK.WeizhengX.et al (2009). In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose) polymerase inhibitor E7016. Clin. Cancer Res.15 (2), 607–612. 10.1158/1078-0432.CCR-08-2079

  • CrossRef
  • Google Scholar

• 325

  SaddoughiS. A.GencerS.PetersonY. K.WardK. E.MukhopadhyayA.OaksJ.et al (2013). Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol. Med.5 (1), 105–121. 10.1002/emmm.201201283

  • CrossRef
  • Google Scholar

• 326

  SafiR.NelsonE. R.ChitneniS. K.FranzK. J.GeorgeD. J.ZalutskyM. R.et al (2014). Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res.74 (20), 5819–5831. 10.1158/0008-5472.CAN-13-3527

  • CrossRef
  • Google Scholar

• 327

  SaghatelyanT.TananyanA.JanoyanN.TadevosyanA.PetrosyanH.HovhannisyanA.et al (2020). Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: a comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine70, 153218. 10.1016/j.phymed.2020.153218

  • CrossRef
  • Google Scholar

• 328

  SahaS.PanigrahiD. P.PatilS.BhutiaS. K. (2018). Autophagy in health and disease: a comprehensive review. Biomed. Pharmacother.104, 485–495. 10.1016/j.biopha.2018.05.007

  • CrossRef
  • Google Scholar

• 329

  SalazarR.Garcia-CarboneroR.LibuttiS. K.HendifarA. E.CustodioA.GuimbaudR.et al (2018). Phase II study of BEZ235 versus everolimus in patients with mammalian target of rapamycin inhibitor-naive advanced pancreatic neuroendocrine tumors. Oncologist23 (7), 766–e90. 10.1634/theoncologist.2017-0144

  • CrossRef
  • Google Scholar

• 330

  SandhuS. K.SchelmanW. R.WildingG.MorenoV.BairdR. D.MirandaS.et al (2013). The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol.14 (9), 882–892. 10.1016/S1470-2045(13)70240-7

  • CrossRef
  • Google Scholar

• 331

  SariA. N.ElwakeelA.DhanjalJ. K.KumarV.SundarD.KaulS. C.et al (2021). Identification and characterization of mortaparib(plus)-A novel triazole derivative that targets mortalin-p53 interaction and inhibits cancer-cell proliferation by wild-type p53-dependent and -independent mechanisms. Cancers (Basel)13 (4), 835. 10.3390/cancers13040835

  • CrossRef
  • Google Scholar

• 332

  SatoH.HirakiM.NambaT.EgawaN.BabaK.TanakaT.et al (2018). Andrographolide induces degradation of mutant p53 via activation of Hsp70. Int. J. Oncol.53 (2), 761–770. 10.3892/ijo.2018.4416

  • CrossRef
  • Google Scholar

• 333

  SattaT.GrantS. (2020). Enhancing venetoclax activity in hematological malignancies. Expert Opin. Investig. Drugs29 (7), 697–708. 10.1080/13543784.2020.1789588

  • CrossRef
  • Google Scholar

• 334

  SayyidR. K.BernardinoR.ChavarriagaJ.GleaveA.KumarR.FleshnerN. E. (2024). Rucaparib monotherapy in the heavily pre-treated metastatic castrate-resistant prostate cancer setting: practical considerations and alternate treatment approaches. Transl. Androl. Urol.13 (5), 884–888. 10.21037/tau-23-671

  • CrossRef
  • Google Scholar

• 335

  SchroderM.KaufmanR. J. (2005). ER stress and the unfolded protein response. Mutat. Res.569 (1-2), 29–63. 10.1016/j.mrfmmm.2004.06.056

  • CrossRef
  • Google Scholar

• 336

  SciegienkaS. J.SolstS. R.FallsK. C.SchoenfeldJ. D.KlingerA. R.RossN. L.et al (2017). D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H(2)O(2)-mediated oxidative stress. Free Radic. Biol. Med.108, 354–361. 10.1016/j.freeradbiomed.2017.04.001

  • CrossRef
  • Google Scholar

• 337

  SecchieroP.BoscoR.CeleghiniC.ZauliG. (2011). Recent advances in the therapeutic perspectives of Nutlin-3. Curr. Pharm. Des.17 (6), 569–577. 10.2174/138161211795222586

  • CrossRef
  • Google Scholar

• 338

  SeehawerM.HeinzmannF.D'ArtistaL.HarbigJ.RouxP. F.HoenickeL.et al (2018). Necroptosis microenvironment directs lineage commitment in liver cancer. Nature562 (7725), 69–75. 10.1038/s41586-018-0519-y

  • CrossRef
  • Google Scholar

• 339

  SeverR.BruggeJ. S. (2015). Signal transduction in cancer. Cold Spring Harb. Perspect. Med.5 (4), a006098. 10.1101/cshperspect.a006098

  • CrossRef
  • Google Scholar

• 340

  ShahM.GreenJ.HudackoR.CohenA. J. (2024). Clinical response to olaparib in a patient with leptomeningeal carcinomatosis in newly diagnosed breast cancer with germline BRCA2 mutation. JCO Precis. Oncol.8, e2400063. 10.1200/PO.24.00063

  • CrossRef
  • Google Scholar

• 341

  Sharifi-RadJ.Herrera-BravoJ.KamilogluS.PetroniK.MishraA. P.Monserrat-MesquidaM.et al (2022). Recent advances in the therapeutic potential of emodin for human health. Biomed. Pharmacother.154, 113555. 10.1016/j.biopha.2022.113555

  • CrossRef
  • Google Scholar

• 342

  SharmaS.de VriesE. G.InfanteJ. R.OldenhuisC. N.GietemaJ. A.YangL.et al (2014). Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors. Invest. New Drugs32 (1), 135–144. 10.1007/s10637-013-9952-9

  • CrossRef
  • Google Scholar

• 343

  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

  • CrossRef
  • Google Scholar

• 344

  ShiJ.ZhaoY.WangY.GaoW.DingJ.LiP.et al (2014a). Inflammatory caspases are innate immune receptors for intracellular LPS. Nature514 (7521), 187–192. 10.1038/nature13683

  • CrossRef
  • Google Scholar

• 345

  ShiY.ZhouF.JiangF.LuH.WangJ.ChengC. (2014b). PARP inhibitor reduces proliferation and increases apoptosis in breast cancer cells. Chin. J. Cancer Res.26 (2), 142–147. 10.3978/j.issn.1000-9604.2014.02.13

  • CrossRef
  • Google Scholar

• 346

  ShimadaK.SkoutaR.KaplanA.YangW. S.HayanoM.DixonS. J.et al (2016). Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol.12 (7), 497–503. 10.1038/nchembio.2079

  • CrossRef
  • Google Scholar

• 347

  ShimadaO.WuX.JinX.NouhM. A.FiscellaM.AlbertV.et al (2007). Human agonistic antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 induces cytotoxicity and apoptosis in prostate cancer and bladder cancer cells. Urology69 (2), 395–401. 10.1016/j.urology.2006.12.007

  • CrossRef
  • Google Scholar

• 348

  ShimonyS.StoneR. M.StahlM. (2022). Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Curr. Opin. Hematol.29 (2), 63–73. 10.1097/MOH.0000000000000698

  • CrossRef
  • Google Scholar

• 349

  SinghJ.NovikY.SteinS.VolmM.MeyersM.SmithJ.et al (2014). Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res.16 (2), R32. 10.1186/bcr3634

  • CrossRef
  • Google Scholar

• 350

  SinhaB. K.MurphyC.BrownS. M.SilverB. B.TokarE. J.BortnerC. D. (2024). Mechanisms of cell death induced by erastin in human ovarian tumor cells. Int. J. Mol. Sci.25 (16), 8666. 10.3390/ijms25168666

  • CrossRef
  • Google Scholar

• 351

  SlamonD. J.DierasV.RugoH. S.HarbeckN.ImS. A.GelmonK. A.et al (2024). Overall survival with palbociclib plus letrozole in advanced breast cancer. J. Clin. Oncol.42 (9), 994–1000. 10.1200/JCO.23.00137

  • CrossRef
  • Google Scholar

• 352

  SoaresJ.EspadinhaM.RaimundoL.RamosH.GomesA. S.GomesS.et al (2017). DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties. Mol. Oncol.11 (6), 612–627. 10.1002/1878-0261.12051

  • CrossRef
  • Google Scholar

• 353

  SonY.AnY.JungJ.ShinS.ParkI.GwakJ.et al (2019). Protopine isolated from Nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53. Phytother. Res.33 (6), 1689–1696. 10.1002/ptr.6357

  • CrossRef
  • Google Scholar

• 354

  SongB.WangW.TangX.GohR. M. W.ThuyaW. L.HoP. C. L.et al (2023). Inhibitory potential of resveratrol in cancer metastasis: from biology to therapy. Cancers (Basel)15 (10), 2758. 10.3390/cancers15102758

  • CrossRef
  • Google Scholar

• 355

  SongM.XiaW.TaoZ.ZhuB.ZhangW.LiuC.et al (2021). Self-assembled polymeric nanocarrier-mediated co-delivery of metformin and doxorubicin for melanoma therapy. Drug Deliv.28 (1), 594–606. 10.1080/10717544.2021.1898703

  • CrossRef
  • Google Scholar

• 356

  SonkusreP. (2019). Specificity of biogenic selenium nanoparticles for prostate cancer therapy with reduced risk of toxicity: an in vitro and in vivo study. Front. Oncol.9, 1541. 10.3389/fonc.2019.01541

  • CrossRef
  • Google Scholar

• 357

  SouersA. J.LeversonJ. D.BoghaertE. R.AcklerS. L.CatronN. D.ChenJ.et al (2013). ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med.19 (2), 202–208. 10.1038/nm.3048

  • CrossRef
  • Google Scholar

• 358

  SpencerB. G.FinnieJ. W. (2020). The role of endoplasmic reticulum stress in cell survival and death. J. Comp. Pathol.181, 86–91. 10.1016/j.jcpa.2020.10.006

  • CrossRef
  • Google Scholar

• 359

  SpringerC.HumayunD.SkoutaR. (2024). Cuproptosis: unraveling the mechanisms of copper-induced cell death and its implication in cancer therapy. Cancers (Basel)16 (3), 647. 10.3390/cancers16030647

  • CrossRef
  • Google Scholar

• 360

  SterlingJ.GutthaS.SongY.SongD.HadziahmetovicM.DunaiefJ. L. (2017). Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels. Exp. Eye Res.155, 15–23. 10.1016/j.exer.2016.12.008

  • CrossRef
  • Google Scholar

• 361

  SuiX.ChenR.WangZ.HuangZ.KongN.ZhangM.et al (2013). Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis.4 (10), e838. 10.1038/cddis.2013.350

  • CrossRef
  • Google Scholar

• 362

  SunJ.WeiQ.ZhouY.WangJ.LiuQ.XuH. (2017). A systematic analysis of FDA-approved anticancer drugs. BMC Syst. Biol.11 (Suppl. 5), 87. 10.1186/s12918-017-0464-7

  • CrossRef
  • Google Scholar

• 363

  SunL.WangH.WangZ.HeS.ChenS.LiaoD.et al (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell148 (1-2), 213–227. 10.1016/j.cell.2011.11.031

  • CrossRef
  • Google Scholar

• 364

  SunW.LiJ. (2024). Efficacy and safety of veliparib in the treatment of advanced/metastatic breast cancer: a meta-analysis of phase II and III randomized controlled trials. J. Chemother.36 (6), 441–448. 10.1080/1120009X.2023.2281760

  • CrossRef
  • Google Scholar

• 365

  SussmanR. T.RicciM. S.HartL. S.SunS. Y.El-DeiryW. S. (2007). Chemotherapy-resistant side-population of colon cancer cells has a higher sensitivity to TRAIL than the non-SP, a higher expression of c-Myc and TRAIL-receptor DR4. Cancer Biol. Ther.6 (9), 1490–1495. 10.4161/cbt.6.9.4905

  • CrossRef
  • Google Scholar

• 366

  SwantonC.BernardE.AbboshC.AndreF.AuwerxJ.BalmainA.et al (2024). Embracing cancer complexity: hallmarks of systemic disease. Cell187 (7), 1589–1616. 10.1016/j.cell.2024.02.009

  • CrossRef
  • Google Scholar

• 367

  TadeleD. S.RobertsonJ.CrispinR.HerreraM. C.ChlubnovaM.PiechaczykL.et al (2021). A cell competition-based small molecule screen identifies a novel compound that induces dual c-Myc depletion and p53 activation. J. Biol. Chem.296, 100179. 10.1074/jbc.RA120.015285

  • CrossRef
  • Google Scholar

• 368

  TammI.KornblauS. M.SegallH.KrajewskiS.WelshK.KitadaS.et al (2000). Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin. Cancer Res.6 (5), 1796–1803.

  • Google Scholar

• 369

  TanT.LiJ.LuoR.WangR.YinL.LiuM.et al (2021). Recent advances in understanding the mechanisms of elemene in reversing drug resistance in tumor cells: a review. Molecules26 (19), 5792. 10.3390/molecules26195792

  • CrossRef
  • Google Scholar

• 370

  TangD.KangR.BergheT. V.VandenabeeleP.KroemerG. (2019). The molecular machinery of regulated cell death. Cell Res.29 (5), 347–364. 10.1038/s41422-019-0164-5

  • CrossRef
  • Google Scholar

• 371

  TangF.HuP.YangZ.XueC.GongJ.SunS.et al (2017). SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways. Oncol. Rep.37 (6), 3449–3458. 10.3892/or.2017.5635

  • CrossRef
  • Google Scholar

• 372

  TangM.CrownJ.DuffyM. J. (2023). Degradation of MYC by the mutant p53 reactivator drug, COTI-2 in breast cancer cells. Invest. New Drugs41 (4), 541–550. 10.1007/s10637-023-01368-1

  • CrossRef
  • Google Scholar

• 373

  TangR.XuJ.ZhangB.LiuJ.LiangC.HuaJ.et al (2020). Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J. Hematol. Oncol.13 (1), 110. 10.1186/s13045-020-00946-7

  • CrossRef
  • Google Scholar

• 374

  TaniguchiK.YamachikaS.HeF.KarinM. (2016). p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett.590 (15), 2375–2397. 10.1002/1873-3468.12301

  • CrossRef
  • Google Scholar

• 375

  TaoZ.Le BlancJ. M.WangC.ZhanT.ZhuangH.WangP.et al (2016). Coadministration of trametinib and palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo. Clin. Cancer Res.22 (1), 122–133. 10.1158/1078-0432.CCR-15-0589

  • CrossRef
  • Google Scholar

• 376

  TelliM. L.LittonJ. K.BeckJ. T.JonesJ. M.AndersenJ.MinaL. A.et al (2024). Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status. Breast Cancer31 (5), 886–897. 10.1007/s12282-024-01603-4

  • CrossRef
  • Google Scholar

• 377

  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

  • CrossRef
  • Google Scholar

• 378

  TrapaniJ. A.SmythM. J. (2002). Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol.2 (10), 735–747. 10.1038/nri911

  • CrossRef
  • Google Scholar

• 379

  TrarbachT.MoehlerM.HeinemannV.KohneC. H.PrzyborekM.SchulzC.et al (2010). Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br. J. Cancer102 (3), 506–512. 10.1038/sj.bjc.6605507

  • CrossRef
  • Google Scholar

• 380

  TronA. E.BelmonteM. A.AdamA.AquilaB. M.BoiseL. H.ChiarparinE.et al (2018). Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun.9 (1), 5341. 10.1038/s41467-018-07551-w

  • CrossRef
  • Google Scholar

• 381

  TsangT.GuX.DavisC. I.PosimoJ. M.MillerZ. A.BradyD. C. (2022). BRAFV600E-Driven lung adenocarcinoma requires copper to sustain autophagic signaling and processing. Mol. Cancer Res.20 (7), 1096–1107. 10.1158/1541-7786.MCR-21-0250

  • CrossRef
  • Google Scholar

• 382

  TseC.ShoemakerA. R.AdickesJ.AndersonM. G.ChenJ.JinS.et al (2008). ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res.68 (9), 3421–3428. 10.1158/0008-5472.CAN-07-5836

  • CrossRef
  • Google Scholar

• 383

  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

  • CrossRef
  • Google Scholar

• 384

  TsvetkovP.DetappeA.CaiK.KeysH. R.BruneZ.YingW.et al (2019). Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat. Chem. Biol.15 (7), 681–689. 10.1038/s41589-019-0291-9

  • CrossRef
  • Google Scholar

• 385

  TucciM.StucciS.SavonarolaA.RestaL.CivesM.RossiR.et al (2014). An imbalance between Beclin-1 and p62 expression promotes the proliferation of myeloma cells through autophagy regulation. Exp. Hematol.42 (10), 897–908. 10.1016/j.exphem.2014.06.005

  • CrossRef
  • Google Scholar

• 386

  TufailM.HuJ. J.LiangJ.HeC. Y.WanW. D.HuangY. Q.et al (2024). Hallmarks of cancer resistance. iScience27 (6), 109979. 10.1016/j.isci.2024.109979

  • CrossRef
  • Google Scholar

• 387

  TzifiF.EconomopoulouC.GourgiotisD.ArdavanisA.PapageorgiouS.ScorilasA. (2012). The role of BCL2 family of apoptosis regulator proteins in acute and chronic leukemias. Adv. Hematol.2012, 524308. 10.1155/2012/524308

  • CrossRef
  • Google Scholar

• 388

  VandenabeeleP.GalluzziL.Vanden BergheT.KroemerG. (2010). Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell Biol.11 (10), 700–714. 10.1038/nrm2970

  • CrossRef
  • Google Scholar

• 389

  Van HoeckeL.RiedererS.SaelensX.SutterG.RojasJ. J. (2020). Recombinant viruses delivering the necroptosis mediator MLKL induce a potent antitumor immunity in mice. Oncoimmunology9 (1), 1802968. 10.1080/2162402X.2020.1802968

  • CrossRef
  • Google Scholar

• 390

  VarisliL.CenO.VlahopoulosS. (2020). Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways. Immunology159 (3), 257–278. 10.1111/imm.13160

  • CrossRef
  • Google Scholar

• 391

  ViswanathanV. S.RyanM. J.DhruvH. D.GillS.EichhoffO. M.Seashore-LudlowB.et al (2017). Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature547 (7664), 453–457. 10.1038/nature23007

  • CrossRef
  • Google Scholar

• 392

  VoglD. T.StadtmauerE. A.TanK. S.HeitjanD. F.DavisL. E.PontiggiaL.et al (2014). Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy10 (8), 1380–1390. 10.4161/auto.29264

  • CrossRef
  • Google Scholar

• 393

  von PawelJ.HarveyJ. H.SpigelD. R.DediuM.ReckM.CebotaruC. L.et al (2014). Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clin. Lung Cancer15 (3), 188–196. 10.1016/j.cllc.2013.12.005

  • CrossRef
  • Google Scholar

• 394

  VuorinenR. L.PaunuN.Turpeenniemi-HujanenT.ReunamoT.JekunenA.KatajaV.et al (2019). Sunitinib first-line treatment in metastatic renal cell carcinoma: costs and effects. Anticancer Res.39 (10), 5559–5564. 10.21873/anticanres.13749

  • CrossRef
  • Google Scholar

• 395

  WaartsM. R.StonestromA. J.ParkY. C.LevineR. L. (2022). Targeting mutations in cancer. J. Clin. Invest.132 (8), e154943. 10.1172/JCI154943

  • CrossRef
  • Google Scholar

• 396

  WalenskyL. D.KungA. L.EscherI.MaliaT. J.BarbutoS.WrightR. D.et al (2004). Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science305 (5689), 1466–1470. 10.1126/science.1099191

  • CrossRef
  • Google Scholar

• 397

  WangC.YouleR. J. (2009). The role of mitochondria in apoptosis. Annu. Rev. Genet.43, 95–118. 10.1146/annurev-genet-102108-134850

  • CrossRef
  • Google Scholar

• 398

  WangF.GouttiaO. G.WangL.PengA. (2021a). PARP1 upregulation in recurrent oral cancer and treatment resistance. Front. Cell Dev. Biol.9, 804962. 10.3389/fcell.2021.804962

  • CrossRef
  • Google Scholar

• 399

  WangH.RongX.ZhaoG.ZhouY.XiaoY.MaD.et al (2022a). The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab.34 (4), 581–594.e8. 10.1016/j.cmet.2022.02.010

  • CrossRef
  • Google Scholar

• 400

  WangH.SunL.SuL.RizoJ.LiuL.WangL. F.et al (2014). Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell54 (1), 133–146. 10.1016/j.molcel.2014.03.003

  • CrossRef
  • Google Scholar

• 401

  WangK.ZhangZ.TsaiH. I.LiuY.GaoJ.WangM.et al (2021b). Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ.28 (4), 1222–1236. 10.1038/s41418-020-00644-4

  • CrossRef
  • Google Scholar

• 402

  WangL.LiK.LinX.YaoZ.WangS.XiongX.et al (2019a). Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis. Cancer Lett.450, 22–31. 10.1016/j.canlet.2019.02.014

  • CrossRef
  • Google Scholar

• 403

  WangQ.ImamuraR.MotaniK.KushiyamaH.NagataS.SudaT. (2013). Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. Int. Immunol.25 (6), 363–372. 10.1093/intimm/dxs161

  • CrossRef
  • Google Scholar

• 404

  WangQ.RenM.FengF.ChenK.JuX. (2018a). Treatment of colon cancer with liver X receptor agonists induces immunogenic cell death. Mol. Carcinog.57 (7), 903–910. 10.1002/mc.22811

  • CrossRef
  • Google Scholar

• 405

  WangQ.ShaoX.ZhangY.ZhuM.WangF. X. C.MuJ.et al (2023). Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Med.12 (10), 11149–11165. 10.1002/cam4.5698

  • CrossRef
  • Google Scholar

• 406

  WangQ.WangP.ZhangL.TessemaM.BaiL.XuX.et al (2020). Epigenetic regulation of RIP3 suppresses necroptosis and increases resistance to chemotherapy in NonSmall cell lung cancer. Transl. Oncol.13 (2), 372–382. 10.1016/j.tranon.2019.11.011

  • CrossRef
  • Google Scholar

• 407

  WangQ.ZhouJ.ChengA.LiuY.GuoJ.LiX.et al (2024a). Artesunate-binding FABP5 promotes apoptosis in lung cancer cells via the PPARγ-SCD pathway. Int. Immunopharmacol.143 (Pt 1), 113381. 10.1016/j.intimp.2024.113381

  • CrossRef
  • Google Scholar

• 408

  WangT.LiuY.LiQ.LuoY.LiuD.LiB. (2022b). Cuproptosis-related gene FDX1 expression correlates with the prognosis and tumor immune microenvironment in clear cell renal cell carcinoma. Front. Immunol.13, 999823. 10.3389/fimmu.2022.999823

  • CrossRef
  • Google Scholar

• 409

  WangW.GreenM.ChoiJ. E.GijonM.KennedyP. D.JohnsonJ. K.et al (2019b). CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature569 (7755), 270–274. 10.1038/s41586-019-1170-y

  • CrossRef
  • Google Scholar

• 410

  WangW.LuZ.WangM.LiuZ.WuB.YangC.et al (2022c). The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma. Front. Immunol.13, 998236. 10.3389/fimmu.2022.998236

  • CrossRef
  • Google Scholar

• 411

  WangW.ZhangL.SunZ. (2022d). Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies. Cancer Biol. Med.19 (7), 948–964. 10.20892/j.issn.2095-3941.2022.0049

  • CrossRef
  • Google Scholar

• 412

  WangX.ChenY.WangX.TianH.WangY.JinJ.et al (2021c). Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res.81 (20), 5217–5229. 10.1158/0008-5472.CAN-21-0567

  • CrossRef
  • Google Scholar

• 413

  WangX.XuS.ZhangL.ChengX.YuH.BaoJ.et al (2021d). Vitamin C induces ferroptosis in anaplastic thyroid cancer cells by ferritinophagy activation. Biochem. Biophys. Res. Commun.551, 46–53. 10.1016/j.bbrc.2021.02.126

  • CrossRef
  • Google Scholar

• 414

  WangY.ChenY.ZhangJ.YangY.FleishmanJ. S.WangY.et al (2024b). Cuproptosis: a novel therapeutic target for overcoming cancer drug resistance. Drug Resist Updat72, 101018. 10.1016/j.drup.2023.101018

  • CrossRef
  • Google Scholar

• 415

  WangY.LuoW.WangY. (2019c). PARP-1 and its associated nucleases in DNA damage response. DNA Repair (Amst)81, 102651. 10.1016/j.dnarep.2019.102651

  • CrossRef
  • Google Scholar

• 416

  WangY.PengR. Q.LiD. D.DingY.WuX. Q.ZengY. X.et al (2011). Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells. Chin. J. Cancer30 (10), 690–700. 10.5732/cjc.011.10056

  • CrossRef
  • Google Scholar

• 417

  WangY.YinB.LiD.WangG.HanX.SunX. (2018b). GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochem. Biophys. Res. Commun.495 (1), 1418–1425. 10.1016/j.bbrc.2017.11.156

  • CrossRef
  • Google Scholar

• 418

  WangY.ZhangL.ZhouF. (2022e). Cuproptosis: a new form of programmed cell death. Cell Mol. Immunol.19 (8), 867–868. 10.1038/s41423-022-00866-1

  • CrossRef
  • Google Scholar

• 419

  WangY. H.ScaddenD. T. (2015). Harnessing the apoptotic programs in cancer stem-like cells. EMBO Rep.16 (9), 1084–1098. 10.15252/embr.201439675

  • CrossRef
  • Google Scholar

• 420

  WangZ.YaoJ.DongT.NiuX. (2022f). Definition of a novel cuproptosis-relevant lncRNA signature for uncovering distinct survival, genomic alterations, and treatment implications in lung adenocarcinoma. J. Immunol. Res.2022, 2756611. 10.1155/2022/2756611

  • CrossRef
  • Google Scholar

• 421

  WeiA. H.RobertsA. W.SpencerA.RosenbergA. S.SiegelD.WalterR. B.et al (2020). Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev.44, 100672. 10.1016/j.blre.2020.100672

  • CrossRef
  • Google Scholar

• 422

  WeiX.XieF.ZhouX.WuY.YanH.LiuT.et al (2022). Role of pyroptosis in inflammation and cancer. Cell Mol. Immunol.19 (9), 971–992. 10.1038/s41423-022-00905-x

  • CrossRef
  • Google Scholar

• 423

  WertzI. E.KusamS.LamC.OkamotoT.SandovalW.AndersonD. J.et al (2011). Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature471 (7336), 110–114. 10.1038/nature09779

  • CrossRef
  • Google Scholar

• 424

  WiddenH.PlaczekW. J. (2021). The multiple mechanisms of MCL1 in the regulation of cell fate. Commun. Biol.4 (1), 1029. 10.1038/s42003-021-02564-6

  • CrossRef
  • Google Scholar

• 425

  Wise-DraperT. M.MoorthyG.SalkeniM. A.KarimN. A.ThomasH. E.MercerC. A.et al (2017). A phase ib study of the dual PI3K/mTOR inhibitor dactolisib (BEZ235) combined with everolimus in patients with advanced solid malignancies. Target Oncol.12 (3), 323–332. 10.1007/s11523-017-0482-9

  • CrossRef
  • Google Scholar

• 426

  WolpinB. M.RubinsonD. A.WangX.ChanJ. A.ClearyJ. M.EnzingerP. C.et al (2014). Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist19 (6), 637–638. 10.1634/theoncologist.2014-0086

  • CrossRef
  • Google Scholar

• 427

  WorkenheS. T.NguyenA.BakhshinyanD.WeiJ.HareD. N.MacNeillK. L.et al (2020). De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors. Commun. Biol.3 (1), 645. 10.1038/s42003-020-01362-w

  • CrossRef
  • Google Scholar

• 428

  WuF.HuangF.JiangN.SuJ.YaoS.LiangB.et al (2024a). Identification of ferroptosis related genes and pathways in prostate cancer cells under erastin exposure. BMC Urol.24 (1), 78. 10.1186/s12894-024-01472-1

  • CrossRef
  • Google Scholar

• 429

  WuH.LinJ.LiuP.HuangZ.ZhaoP.JinH.et al (2015). Is the autophagy a friend or foe in the silver nanoparticles associated radiotherapy for glioma?Biomaterials62, 47–57. 10.1016/j.biomaterials.2015.05.033

  • CrossRef
  • Google Scholar

• 430

  WuM.WangY.YangD.GongY.RaoF.LiuR.et al (2019a). A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma. EBioMedicine41, 244–255. 10.1016/j.ebiom.2019.02.012

  • CrossRef
  • Google Scholar

• 431

  WuW.LiuP.LiJ. (2012). Necroptosis: an emerging form of programmed cell death. Crit. Rev. Oncol. Hematol.82 (3), 249–258. 10.1016/j.critrevonc.2011.08.004

  • CrossRef
  • Google Scholar

• 432

  WuX.ZhuJ.YinR.YangJ.LiuJ.WangJ.et al (2024b). Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial. EClinicalMedicine72, 102629. 10.1016/j.eclinm.2024.102629

  • CrossRef
  • Google Scholar

• 433

  WuY.DongG.ShengC. (2020). Targeting necroptosis in anticancer therapy: mechanisms and modulators. Acta Pharm. Sin. B10 (9), 1601–1618. 10.1016/j.apsb.2020.01.007

  • CrossRef
  • Google Scholar

• 434

  WuZ.ZhangW.KangY. J. (2019b). Copper affects the binding of HIF-1α to the critical motifs of its target genes. Metallomics11 (2), 429–438. 10.1039/c8mt00280k

  • CrossRef
  • Google Scholar

• 435

  XieJ.YangY.GaoY.HeJ. (2023a). Cuproptosis: mechanisms and links with cancers. Mol. Cancer22 (1), 46. 10.1186/s12943-023-01732-y

  • CrossRef
  • Google Scholar

• 436

  XieY.KangR.KlionskyD. J.TangD. (2023b). GPX4 in cell death, autophagy, and disease. Autophagy19 (10), 2621–2638. 10.1080/15548627.2023.2218764

  • CrossRef
  • Google Scholar

• 437

  XieY.ZhuS.SongX.SunX.FanY.LiuJ.et al (2017). The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep.20 (7), 1692–1704. 10.1016/j.celrep.2017.07.055

  • CrossRef
  • Google Scholar

• 438

  XuY.LiuS. Y.ZengL.MaH.ZhangY.YangH.et al (2022). An enzyme-engineered nonporous copper(I) coordination polymer nanoplatform for cuproptosis-based synergistic cancer therapy. Adv. Mater34 (43), e2204733. 10.1002/adma.202204733

  • CrossRef
  • Google Scholar

• 439

  XuzhangW.LuT.JinW.YuY.LiZ.ShenL.et al (2024). Cisplatin-induced pyroptosis enhances the efficacy of PD-L1 inhibitor in small-cell lung cancer via GSDME/IL12/CD4Tem Axis. Int. J. Biol. Sci.20 (2), 537–553. 10.7150/ijbs.89080

  • CrossRef
  • Google Scholar

• 440

  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

  • CrossRef
  • Google Scholar

• 441

  YanJ.WanP.ChoksiS.LiuZ. G. (2022). Necroptosis and tumor progression. Trends Cancer8 (1), 21–27. 10.1016/j.trecan.2021.09.003

  • CrossRef
  • Google Scholar

• 442

  YangB.JiangJ.WuH.LuQ. (2024). Topical BCl-2 inhibitor (ABT-737) attenuates skin photoaging in mice. Exp. Dermatol33 (3), e15051. 10.1111/exd.15051

  • CrossRef
  • Google Scholar

• 443

  YangD.ShuT.ZhaoH.SunY.XuW.TuG. (2020). Knockdown of macrophage migration inhibitory factor (MIF), a novel target to protect neurons from parthanatos induced by simulated post-spinal cord injury oxidative stress. Biochem. Biophys. Res. Commun.523 (3), 719–725. 10.1016/j.bbrc.2019.12.115

  • CrossRef
  • Google Scholar

• 444

  YangL.KumarB.ShenC.ZhaoS.BlakajD.LiT.et al (2019). LCL161, a SMAC-mimetic, preferentially radiosensitizes human papillomavirus-negative head and neck squamous cell carcinoma. Mol. Cancer Ther.18 (6), 1025–1035. 10.1158/1535-7163.MCT-18-1157

  • CrossRef
  • Google Scholar

• 445

  YangM.WuX.HuJ.WangY.WangY.ZhangL.et al (2022). COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma. J. Hepatol.76 (5), 1138–1150. 10.1016/j.jhep.2022.01.009

  • CrossRef
  • Google Scholar

• 446

  YangW. S.SriRamaratnamR.WelschM. E.ShimadaK.SkoutaR.ViswanathanV. S.et al (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell156 (1-2), 317–331. 10.1016/j.cell.2013.12.010

  • CrossRef
  • Google Scholar

• 447

  YangY.HuW.FengS.MaJ.WuM. (2005). RIP3 beta and RIP3 gamma, two novel splice variants of receptor-interacting protein 3 (RIP3), downregulate RIP3-induced apoptosis. Biochem. Biophys. Res. Commun.332 (1), 181–187. 10.1016/j.bbrc.2005.04.114

  • CrossRef
  • Google Scholar

• 448

  YaoX.XieR.CaoY.TangJ.MenY.PengH.et al (2021). Simvastatin induced ferroptosis for triple-negative breast cancer therapy. J. Nanobiotechnology19 (1), 311. 10.1186/s12951-021-01058-1

  • CrossRef
  • Google Scholar

• 449

  YeK.ChenZ.XuY. (2023). The double-edged functions of necroptosis. Cell Death Dis.14 (2), 163. 10.1038/s41419-023-05691-6

  • CrossRef
  • Google Scholar

• 450

  YeL.JinF.KumarS. K.DaiY. (2021a). The mechanisms and therapeutic targets of ferroptosis in cancer. Expert Opin. Ther. Targets25 (11), 965–986. 10.1080/14728222.2021.2011206

  • CrossRef
  • Google Scholar

• 451

  YeL. F.ChaudharyK. R.ZandkarimiF.HarkenA. D.KinslowC. J.UpadhyayulaP. S.et al (2020). Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem. Biol.15 (2), 469–484. 10.1021/acschembio.9b00939

  • CrossRef
  • Google Scholar

• 452

  YeZ. Q.ChenH. B.ZhangT. Y.ChenZ.TianL.GuD. N. (2021b). MicroRNA-7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF-κB signaling in pancreatic cancer cells. Oncol. Lett.21 (2), 139. 10.3892/ol.2020.12400

  • CrossRef
  • Google Scholar

• 453

  YoshiiJ.YoshijiH.KuriyamaS.IkenakaY.NoguchiR.OkudaH.et al (2001). The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells. Int. J. Cancer94 (6), 768–773. 10.1002/ijc.1537

  • CrossRef
  • Google Scholar

• 454

  YounesA.VoseJ. M.ZelenetzA. D.SmithM. R.BurrisH. A.AnsellS. M.et al (2010). A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br. J. Cancer103 (12), 1783–1787. 10.1038/sj.bjc.6605987

  • CrossRef
  • Google Scholar

• 455

  YuJ.LiS.QiJ.ChenZ.WuY.GuoJ.et al (2019). Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell Death Dis.10 (3), 193. 10.1038/s41419-019-1441-4

  • CrossRef
  • Google Scholar

• 456

  YuX.DengQ.LiW.XiaoL.LuoX.LiuX.et al (2015). Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFα and ROS production. Oncotarget6 (4), 1995–2008. 10.18632/oncotarget.3038

  • CrossRef
  • Google Scholar

• 457

  YuX.HeS. (2017). GSDME as an executioner of chemotherapy-induced cell death. Sci. China Life Sci.60 (11), 1291–1294. 10.1007/s11427-017-9142-2

  • CrossRef
  • Google Scholar

• 458

  YuanB.LiaoF.ShiZ. Z.RenY.DengX. L.YangT. T.et al (2020). Dihydroartemisinin inhibits the proliferation, colony formation and induces ferroptosis of lung cancer cells by inhibiting PRIM2/slc7a11 Axis. Onco Targets Ther.13, 10829–10840. 10.2147/OTT.S248492

  • CrossRef
  • Google Scholar

• 459

  YuanJ.SongJ.ChenC.LvX.BaiJ.YangJ.et al (2022). Combination of ruxolitinib with ABT-737 exhibits synergistic effects in cells carrying concurrent JAK2(V617F) and ASXL1 mutations. Invest. New Drugs40 (6), 1194–1205. 10.1007/s10637-022-01297-5

  • CrossRef
  • Google Scholar

• 460

  YueE.TuguzbaevaG.ChenX.QinY.LiA.SunX.et al (2019). Anthocyanin is involved in the activation of pyroptosis in oral squamous cell carcinoma. Phytomedicine56, 286–294. 10.1016/j.phymed.2018.09.223

  • CrossRef
  • Google Scholar

• 461

  YunJ.MullarkyE.LuC.BoschK. N.KavalierA.RiveraK.et al (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science350 (6266), 1391–1396. 10.1126/science.aaa5004

  • CrossRef
  • Google Scholar

• 462

  ZanardiE.VerzoniE.GrassiP.NecchiA.GiannatempoP.RaggiD.et al (2015). Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma. Ther. Adv. Urol.7 (3), 152–161. 10.1177/1756287215574457

  • CrossRef
  • Google Scholar

• 463

  ZhangC.LiuX.JinS.ChenY.GuoR. (2022a). Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol. Cancer21 (1), 47. 10.1186/s12943-022-01530-y

  • CrossRef
  • Google Scholar

• 464

  ZhangC. C.LiC. G.WangY. F.XuL. H.HeX. H.ZengQ. Z.et al (2019a). Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis24 (3-4), 312–325. 10.1007/s10495-019-01515-1

  • CrossRef
  • Google Scholar

• 465

  ZhangD.CuiP.DaiZ.YangB.YaoX.LiuQ.et al (2019b). Tumor microenvironment responsive FePt/MoS(2) nanocomposites with chemotherapy and photothermal therapy for enhancing cancer immunotherapy. Nanoscale11 (42), 19912–19922. 10.1039/c9nr05684j

  • CrossRef
  • Google Scholar

• 466

  ZhangJ.YuG.YangY.WangY.GuoM.YinQ.et al (2022b). A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis. Pharmacol. Res.177, 106128. 10.1016/j.phrs.2022.106128

  • CrossRef
  • Google Scholar

• 467

  ZhangN.HartigH.DzhagalovI.DraperD.HeY. W. (2005). The role of apoptosis in the development and function of T lymphocytes. Cell Res.15 (10), 749–769. 10.1038/sj.cr.7290345

  • CrossRef
  • Google Scholar

• 468

  ZhangT.YinC.FedorovA.QiaoL.BaoH.BeknazarovN.et al (2022c). ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature606 (7914), 594–602. 10.1038/s41586-022-04753-7

  • CrossRef
  • Google Scholar

• 469

  ZhangX.WalkeG. R.HorvathI.KumarR.BlockhuysS.HolgerssonS.et al (2022d). Memo1 binds reduced copper ions, interacts with copper chaperone Atox1, and protects against copper-mediated redox activity in vitro. Proc. Natl. Acad. Sci. U. S. A.119 (37), e2206905119. 10.1073/pnas.2206905119

  • CrossRef
  • Google Scholar

• 470

  ZhangX.WangH.YuM.MaK.NingL. (2022e). Inhibition of autophagy by 3-methyladenine promotes migration and invasion of colon cancer cells through epithelial mesenchymal transformation. Transl. Cancer Res.11 (8), 2834–2842. 10.21037/tcr-22-1736

  • CrossRef
  • Google Scholar

• 471

  ZhangY.ChenX.GueydanC.HanJ. (2018). Plasma membrane changes during programmed cell deaths. Cell Res.28 (1), 9–21. 10.1038/cr.2017.133

  • CrossRef
  • Google Scholar

• 472

  ZhangY.TanH.DanielsJ. D.ZandkarimiF.LiuH.BrownL. M.et al (2019c). Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol.26 (5), 623–633. 10.1016/j.chembiol.2019.01.008

  • CrossRef
  • Google Scholar

• 473

  ZhangZ.LinJ.YangL.LiY. (2023). Osimertinib inhibits brain metastases and improves long-term survival in a patient with advanced squamous cell lung cancer: a case report and literature review. Front. Oncol.13, 1188772. 10.3389/fonc.2023.1188772

  • CrossRef
  • Google Scholar

• 474

  ZhangZ.ZengX.WuY.LiuY.ZhangX.SongZ. (2022f). Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in hepatocellular carcinoma. Front. Immunol.13, 925618. 10.3389/fimmu.2022.925618

  • CrossRef
  • Google Scholar

• 475

  ZhaoG.FengE.LiuY. (2023). Efficacy and safety of veliparib combined with traditional chemotherapy for treating patients with lung cancer: a comprehensive review and meta-analysis. PeerJ11, e16402. 10.7717/peerj.16402

  • CrossRef
  • Google Scholar

• 476

  ZhaoG.HanX.ZhengS.LiZ.ShaY.NiJ.et al (2016). Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol. Rep.35 (2), 1065–1074. 10.3892/or.2015.4413

  • CrossRef
  • Google Scholar

• 477

  ZhaoL.ZhouX.XieF.ZhangL.YanH.HuangJ.et al (2022). Ferroptosis in cancer and cancer immunotherapy. Cancer Commun. (Lond)42 (2), 88–116. 10.1002/cac2.12250

  • CrossRef
  • Google Scholar

• 478

  ZhaoW.JiangL.FangT.FangF.LiuY.ZhaoY.et al (2021a). β-Lapachone selectively kills hepatocellular carcinoma cells by targeting NQO1 to induce extensive DNA damage and PARP1 hyperactivation. Front. Oncol.11, 747282. 10.3389/fonc.2021.747282

  • CrossRef
  • Google Scholar

• 479

  ZhaoX.QuanJ.TanY.LiuY.LiaoC.LiZ.et al (2021b). RIP3 mediates TCN-induced necroptosis through activating mitochondrial metabolism and ROS production in chemotherapy-resistant cancers. Am. J. Cancer Res.11 (3), 729–745.

  • Google Scholar

• 480

  ZhengD.LiwinskiT.ElinavE. (2020a). Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discov.6, 36. 10.1038/s41421-020-0167-x

  • CrossRef
  • Google Scholar

• 481

  ZhengM.WilliamsE. P.MalireddiR. K. S.KarkiR.BanothB.BurtonA.et al (2020b). Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection. J. Biol. Chem.295 (41), 14040–14052. 10.1074/jbc.RA120.015036

  • CrossRef
  • Google Scholar

• 482

  ZhengZ.BianY.ZhangY.RenG.LiG. (2020c). Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle19 (10), 1089–1104. 10.1080/15384101.2020.1743911

  • CrossRef
  • Google Scholar

• 483

  ZhengZ.LiG. (2020). Mechanisms and therapeutic regulation of pyroptosis in inflammatory diseases and cancer. Int. J. Mol. Sci.21 (4), 1456. 10.3390/ijms21041456

  • CrossRef
  • Google Scholar

• 484

  ZhouJ.LiG.HanG.FengS.LiuY.ChenJ.et al (2020). Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway. Invest. New Drugs38 (1), 50–59. 10.1007/s10637-019-00764-w

  • CrossRef
  • Google Scholar

• 485

  ZhouJ.YuQ.SongJ.LiS.LiX. L.KangB. K.et al (2023). Photothermally triggered copper payload release for cuproptosis-promoted cancer synergistic therapy. Angew. Chem. Int. Ed. Engl.62 (12), e202213922. 10.1002/anie.202213922

  • CrossRef
  • Google Scholar

• 486

  ZhouQ.MengY.LiD.YaoL.LeJ.LiuY.et al (2024a). Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies. Signal Transduct. Target Ther.9 (1), 55. 10.1038/s41392-024-01769-5

  • CrossRef
  • Google Scholar

• 487

  ZhouY.LiJ.XuX.ZhaoM.ZhangB.DengS.et al (2019). (64)Cu-based radiopharmaceuticals in molecular imaging. Technol. Cancer Res. Treat.18, 1533033819830758. 10.1177/1533033819830758

  • CrossRef
  • Google Scholar

• 488

  ZhouY.LiuL.TaoS.YaoY.WangY.WeiQ.et al (2021). Parthanatos and its associated components: promising therapeutic targets for cancer. Pharmacol. Res.163, 105299. 10.1016/j.phrs.2020.105299

  • CrossRef
  • Google Scholar

• 489

  ZhouY.ManghwarH.HuW.LiuF. (2022). Degradation mechanism of autophagy-related proteins and research progress. Int. J. Mol. Sci.23 (13), 7301. 10.3390/ijms23137301

  • CrossRef
  • Google Scholar

• 490

  ZhouY.TaoL.QiuJ.XuJ.YangX.ZhangY.et al (2024b). Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct. Target Ther.9 (1), 132. 10.1038/s41392-024-01823-2

  • CrossRef
  • Google Scholar

• 491

  ZimnaA.KurpiszM. (2015). Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed. Res. Int.2015, 549412. 10.1155/2015/549412

  • CrossRef
  • Google Scholar