Abstract
Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic.
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References
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Zhang, Y. et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol. 26, 623–633 (2019).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Berndt, C. et al. Ferroptosis in health and disease. Redox Biol. 75, 103211 (2024).
Helberg, J. & Pratt, D. A. Autoxidation vs. antioxidants—the fight for forever. Chem. Soc. Rev. 50, 7343–7358 (2021).
Li, Z., Lange, M., Dixon, S. J. & Olzmann, J. A. Lipid quality control and ferroptosis: from concept to mechanism. Annu. Rev. Biochem. 93, 499–528 (2024).
Sassano, M. L. et al. Endoplasmic reticulum–mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis. Nat. Cell Biol. 27, 902–917 (2025).
Cañeque, T. et al. Activation of lysosomal iron triggers ferroptosis in cancer. Nature 642, 492–500 (2025).
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432 (2019).
von Krusenstiern, A. N. et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat. Chem. Biol. 19, 719–730 (2023).
Magtanong, L. et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem. Biol. 29, 1409–1418 (2022).
Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol. 33, 1282–1294 (2023).
Dai, E., Meng, L., Kang, R., Wang, X. & Tang, D. ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem. Biophys. Res. Commun. 522, 415–421 (2020).
Pedrera, L. et al. Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ. 28, 1644–1657 (2021).
Wu, Y. et al. Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2. Dev. Cell 58, 376–397 (2023).
Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).
Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Liang, D. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186, 2748–2764 (2023).
Rodencal, J. et al. Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest. Cell Chem. Biol. 31, 234–248 (2024).
Tesfay, L. et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 79, 5355–5366 (2019).
Puente-Cobacho, B. et al. De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis. Redox Biol. 80, 103480 (2025).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Eaton, J. K. et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol. 16, 497–506 (2020).
Randolph, J. T. et al. Discovery of a potent chloroacetamide GPX4 inhibitor with bioavailability to enable target engagement in mice, a potential tool compound for inducing ferroptosis in vivo. J. Med. Chem. 66, 3852–3865 (2023).
Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).
Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422 (2018).
Mishima, E. et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E9–E18 (2023).
Mao, C. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586–590 (2021).
Wu, Z. et al. Hydropersulfides inhibit lipid peroxidation and protect cells from ferroptosis. J. Am. Chem. Soc. 144, 15825–15837 (2022).
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Calhoon, D. et al. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis. Nature https://doi.org/10.1038/s41586-025-09162-0 (2025).
Freitas, F. P. et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature 626, 401–410 (2024).
Garcia-Bermudez, J. et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118–122 (2019).
Li, Y. et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 626, 411–418 (2024).
Rademaker, G. et al. PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer. Nature https://doi.org/10.1038/s41586-025-09017-8 (2025).
Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).
Leu, J. I., Murphy, M. E. & George, D. L. Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc. Natl Acad. Sci. USA 116, 8390–8396 (2019).
Barayeu, U. et al. Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals. Nat. Chem. Biol. 19, 28–37 (2023).
Kang, Y. P. et al. Non-canonical glutamate–cysteine ligase activity protects against ferroptosis. Cell Metab. 33, 174–189 (2021).
Zheng, J. & Conrad, M. Ferroptosis: when metabolism meets cell death. Physiol. Rev. 105, 651–706 (2025).
Yang, J.-S. et al. ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1. Cell 188, 2569–2585 (2025).
Chen, L. et al. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat. Metab. 1, 404–415 (2019).
Tsoi, J. et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell 33, 890–904 (2018).
Schwab, A. et al. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat. Cell Biol. 26, 1470–1481 (2024).
Banu, M. A. et al. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma. EMBO J. 43, 4492–4521 (2024).
Bebber, C. M. et al. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat. Commun. 12, 2048 (2021).
Herrera-Abreu, M. T. et al. Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer. Nat. Commun. 15, 9550 (2024).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Kalkavan, H. et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356–3374 (2022).
Riegman, M. et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol. 22, 1042–1048 (2020).
Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).
Co, H. K. C., Wu, C.-C., Lee, Y.-C. & Chen, S.-H. Emergence of large-scale cell death through ferroptotic trigger waves. Nature 631, 654–662 (2024).
Zhang, Q. et al. PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury. Nat. Chem. Biol. 20, 835–846 (2024).
Roeck, B. F. et al. Ferroptosis spreads to neighboring cells via plasma membrane contacts. Nat. Commun. 16, 2951 (2025).
Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling. Nature 572, 402–406 (2019).
Ackermann, T. et al. Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis. EMBO Mol. Med. 16, 2749–2774 (2024).
Bell, H. N., Stockwell, B. R. & Zou, W. Ironing out the role of ferroptosis in immunity. Immunity 57, 941–956 (2024).
Ramakrishnan, R. et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J. Immunol. 192, 2920–2931 (2014).
Wiernicki, B. et al. Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity. Nat. Commun. 13, 3676 (2022).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022).
Yee, P. P. et al. Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat. Commun. 11, 5424 (2020).
Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703 (2023).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).
Lin, H. et al. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. Cancer Cell 42, 2032–2044 (2024).
Drijvers, J. M. et al. Pharmacologic screening identifies metabolic vulnerabilities of CD8+ T cells. Cancer Immunol. Res. 9, 184–199 (2021).
Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).
Muri, J., Thut, H., Bornkamm, G. W. & Kopf, M. B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep. 29, 2731–2744 (2019).
Kim, R., Taylor, D., Vonderheide, R. H. & Gabrilovich, D. I. Ferroptosis of immune cells in the tumor microenvironment. Trends Pharmacol. Sci. 44, 542–552 (2023).
Morgan, P. K. et al. A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility. Nat. Cell Biol. 26, 645–659 (2024).
Timmerman, L. A. et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450–465 (2013).
Arensman, M. D. et al. Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc. Natl Acad. Sci. USA 116, 9533–9542 (2019).
Dixon, S. J. et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014).
Yan, R. et al. The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis. Cell Res. 32, 687–690 (2022).
Chen, Z. et al. PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance. Mol. Cell 84, 4645–4659 (2024).
Ito, J. et al. PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization. Mol. Cell 84, 4629–4644 (2024).
Cramer, S. L. et al. Systemic depletion of l-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat. Med. 23, 120–127 (2017).
Zhang, L. et al. Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11. Proc. Natl Acad. Sci. USA 119, e2122840119 (2022).
Zheng, H. et al. Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance. Nat. Cancer 5, 572–589 (2024).
Armenta, D. A. et al. Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein. Cell Chem. Biol. 29, 1588–1600 (2022).
Moosmayer, D. et al. Crystal structures of the selenoprotein glutathione peroxidase 4 in its apo form and in complex with the covalently bound inhibitor ML162. Acta Crystallogr. D Struct. Biol. 77, 237–248 (2021).
Liu, H. et al. Small-molecule allosteric inhibitors of GPX4. Cell Chem. Biol. 29, 1680–1693 (2022).
Cheff, D. M. et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 62, 102703 (2023).
Gao, J. et al. Selenium-encoded isotopic signature targeted profiling. ACS Cent. Sci. 4, 960–970 (2018).
Wang, M.-E. et al. RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. J. Clin. Invest. 133, e166647 (2023).
Luo, T. et al. Intracellular delivery of glutathione peroxidase degrader induces ferroptosis in vivo. Angew. Chem. Int. Ed. Engl. 61, e202206277 (2022).
Nguyen, K.-A., Conilh, L., Falson, P., Dumontet, C. & Boumendjel, A. The first ADC bearing the ferroptosis inducer RSL3 as a payload with conservation of the fragile electrophilic warhead. Eur. J. Med. Chem. 244, 114863 (2022).
Bailey, H. H. l-S,R-buthionine sulfoximine: historical development and clinical issues. Chem. Biol. Interact. 111–112, 239–254 (1998).
Xavier da Silva, T. N., Schulte, C., Alves, A. N., Maric, H. M. & Friedmann Angeli, J. P. Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules. Cell Death Dis. 14, 281 (2023).
Nakamura, T. et al. Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nat. Struct. Mol. Biol. 30, 1806–1815 (2023).
Cheu, J. W.-S. et al. Ferroptosis suppressor protein 1 inhibition promotes tumor ferroptosis and anti-tumor immune responses in liver cancer. Cell. Mol. Gastroenterol. Hepatol. 16, 133–159 (2023).
Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371–377 (2023).
Hendricks, J. M. et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. 30, 1090–1103 (2023).
Zhang, S. et al. Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1. Proc. Natl Acad. Sci. USA 122, e2505197122 (2025).
Mei, J., Webb, S., Zhang, B. & Shu, H.-B. The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression. Oncogene 25, 849–856 (2006).
Hassannia, B. et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128, 3341–3355 (2018).
Bruedigam, C. et al. Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia. Nat. Cancer 5, 47–65 (2024).
Robe, P. A. et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer 9, 372 (2009).
Bartolacci, C. et al. Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer. Nat. Commun. 13, 4327 (2022).
Llabani, E. et al. Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis. Nat. Chem. 11, 521–532 (2019).
Kim, S. E. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat. Nanotechnol. 11, 977–985 (2016).
Jiang, X. et al. Exogenous dihomo-γ-linolenic acid triggers ferroptosis via ACSL4-mediated lipid metabolic reprogramming in acute myeloid leukemia cells. Transl. Oncol. 52, 102227 (2025).
Perez, M. A., Magtanong, L., Dixon, S. J. & Watts, J. L. Dietary lipids induce ferroptosis in Caenorhabditiselegans and human cancer cells. Dev. Cell 54, 447–454 (2020).
Beatty, A. et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12, 2244 (2021).
Upadhyayula, P. S. et al. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat. Commun. 14, 1187 (2023).
Xue, Y. et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. Nat. Commun. 14, 4758 (2023).
Gao, Y. et al. CAR T cells engineered to secrete IFNκ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Cancer Immunol. Res. 12, 1691–1702 (2024).
Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2, 43ra56 (2010).
Wang, Y. et al. ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization. Cell 188, 412–429 (2025).
Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).
Wang, K. et al. Reactivation of MAPK–SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors. Redox Biol. 78, 103419 (2024).
Zou, Y. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10, 1617 (2019).
Zhang, S. et al. TCP1 expression alters the ferroptosis sensitivity of diffuse large B-cell lymphoma subtypes by stabilising ACSL4 and influences patient prognosis. Cell Death Dis. 15, 611 (2024).
Song, X., Zhang, W., Yu, N. & Zhong, X. PAQR3 facilitates the ferroptosis of diffuse large B-cell lymphoma via the regulation of LDLR-mediated PI3K/AKT pathway. Hematol. Oncol. 42, e3219 (2024).
Floros, K. V. et al. MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc−/glutathione axis. Cancer Res. 81, 1896–1908 (2021).
Lu, Y. et al. MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma. Cell Death Dis. 12, 511 (2021).
Alborzinia, H. et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat. Cancer 3, 471–485 (2022).
Alborzinia, H. et al. LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma. EMBO Mol. Med. 15, e18014 (2023).
Li, Z. et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat. Chem. Biol. 18, 751–761 (2022).
Koppula, P. et al. A targetable CoQ–FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun. 13, 2206 (2022).
Padanad, M. S. et al. Fatty acid oxidation mediated by acyl-CoA synthetase long chain 3 is required for mutant KRAS lung tumorigenesis. Cell Rep. 16, 1614–1628 (2016).
Luo, Z. et al. HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells. Cell Death Dis. 15, 220 (2024).
Schonberg, D. L. et al. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell 28, 441–455 (2015).
Calzolari, A. et al. Transferrin receptor 2 is frequently and highly expressed in glioblastomas. Transl. Oncol. 3, 123–134 (2010).
Jiang, Y., Yu, Y., Pan, Z., Glandorff, C. & Sun, M. Ferroptosis: a new hunter of hepatocellular carcinoma. Cell Death Discov. 10, 136 (2024).
Greene, C. J. et al. Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation. Free Radic. Biol. Med. 133, 295–309 (2019).
Priolo, C. et al. Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma. Proc. Natl Acad. Sci. USA 115, E6274–E6282 (2018).
Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).
de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).
Sokol, K. H. et al. Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking. Cell Chem. Biol. 32, 408–422 (2025).
Zhuang, X. et al. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis. Nature 637, 184–194 (2025).
Wang, F. et al. PALP: a rapid imaging technique for stratifying ferroptosis sensitivity in normal and tumor tissues in situ. Cell Chem. Biol. 29, 157–170 (2022).
Cui, S. et al. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases. Mol. Cell 83, 3931–3939 (2023).
Feng, H. et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 30, 3411–3423 (2020).
Morotti, M. et al. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 629, 426–434 (2024).
Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 9, 1673–1685 (2019).
Ye, L. F. et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem. Biol. 15, 469–484 (2020).
Adjemian, S. et al. Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell Death Dis. 11, 1003 (2020).
Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020).
Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016).
Mullen, N. J. et al. DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation. eLife 12, RP87292 (2024).
Chen, T. et al. Discovery of novel potent covalent glutathione peroxidase 4 inhibitors as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer. J. Med. Chem. 66, 10036–10059 (2023).
Li, J. et al. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci. Transl. Med. 15, eadg3049 (2023).
Xu, S. et al. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc. Natl Acad. Sci. USA 109, 16348–16353 (2012).
Eaton, J. K., Ruberto, R. A., Kramm, A., Viswanathan, V. S. & Schreiber, S. L. Diacylfuroxans are masked nitrile oxides that inhibit GPX4 covalently. J. Am. Chem. Soc. 141, 20407–20415 (2019).
Griffith, O. W. & Meister, A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J. Biol. Chem. 254, 7558–7560 (1979).
Acknowledgements
We thank M. Chaufan, M. Cheah, C. Fraser, A. Gautam, A. Joseph, M. Kaur, S. Manukian, M. Murray and M. Sabatier for their comments on this work. This work was supported by the National Institutes of Health (CA282202 to J.M.U., GM122923 to S.J.D.), the Department of Defense (HT94252310765 to J.M.U.), Find the Cause Breast Cancer Foundation (J.M.U.) and the Ludwig Cancer Center at Harvard (J.M.U.).
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Ubellacker, J.M., Dixon, S.J. Prospects for ferroptosis therapies in cancer. Nat Cancer 6, 1326–1336 (2025). https://doi.org/10.1038/s43018-025-01037-7
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DOI: https://doi.org/10.1038/s43018-025-01037-7
