Abstract
Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.
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References
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Chen, X. et al. A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat. Commun. 13, 6318 (2022).
Amoscato, A. A. et al. Formation of protein adducts with Hydroperoxy–PE electrophilic cleavage products during ferroptosis. Redox Biol. 63, 102758 (2023).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Li, P. et al. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat. Immunol. 22, 1107–1117 (2021).
Amaral, E. P. et al. A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis. J. Exp. Med. 216, 556–570 (2019).
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).
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).
Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).
Dolma, S., Lessnick, S. L., Hahn, W. C. & Stockwell, B. R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003).
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).
Seiler, A. et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237–248 (2008).
Banjac, A. et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 27, 1618–1628 (2008).
Chen, P. H. et al. Zinc transporter ZIP7 is a novel determinant of ferroptosis. Cell Death Dis. 12, 198 (2021).
Xue, Q. et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy 19, 1982–1996 (2023).
Li, J. et al. Tumor heterogeneity in autophagy-dependent ferroptosis. Autophagy 17, 3361–3374 (2021).
Hou, W. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12, 1425–1428 (2016).
Gao, M. et al. Ferroptosis is an autophagic cell death process. Cell Res. 26, 1021–1032 (2016).
Bai, Y. et al. Lipid storage and lipophagy regulates ferroptosis. Biochem. Biophys. Res. Commun. 508, 997–1003 (2019).
Yang, M. et al. Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci. Adv. 5, eaaw2238 (2019).
Tian, R. et al. Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat. Neurosci. 24, 1020–1034 (2021).
Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).
Gao, M. et al. Role of mitochondria in ferroptosis. Mol. Cell 73, 354–363 (2019).
Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001–5011 (2004).
Li, C., Liu, J., Hou, W., Kang, R. & Tang, D. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion. Front. Cell Dev. Biol. 9, 698679 (2021).
Lee, H. et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol. 22, 225–234 (2020).
Song, X. et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc− activity. Curr. Biol. 28, 2388–2399 (2018).
Yang, C. et al. De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat. Cell Biol. 25, 836–847 (2023).
Xie, Y. et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 20, 1692–1704 (2017).
Yan, B. et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81, 355–369 (2020).
Zou, Y. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol. 16, 302–309 (2020).
Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Yuan, H., Li, X., Zhang, X., Kang, R. & Tang, D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem. Biophys. Res. Commun. 478, 1338–1343 (2016).
Dixon, S. J. et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol. 10, 1604–1609 (2015).
Lin, Z. et al. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. Nat. Commun. 13, 7965 (2022).
Liao, P. et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 40, 365–378 (2022).
Zhang, H. L. et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol. 24, 88–98 (2022).
Chen, X. et al. Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis. Autophagy 19, 54–74 (2023).
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432 (2019).
Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl Acad. Sci. USA 113, E4966–E4975 (2016).
Liu, Y. et al. SLC25A22 as a key mitochondrial transporter against ferroptosis by producing glutathione and monounsaturated fatty acids. Antioxid. Redox Signal. 39, 166–185 (2023).
Liang, D. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186, 2748–2764 (2023).
Chu, B. et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat. Cell Biol. 21, 579–591 (2019).
Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).
Xin, S. et al. MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling. Cell Death Differ. 29, 670–686 (2022).
Klasson, T. D. et al. ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma. Cancer Metab. 10, 14 (2022).
Reed, A., Ware, T., Li, H., Fernando Bazan, J. & Cravatt, B. F. TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids. Nat. Chem. Biol. 19, 378–388 (2023).
Liu, J. et al. TMEM164 is a new determinant of autophagy-dependent ferroptosis. Autophagy 19, 945–956 (2023).
Li, C. et al. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy 17, 948–960 (2021).
Nagasaki, T. et al. 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation. J. Clin. Invest. 132, e151685 (2022).
Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641 (2017).
Dar, H. H. et al. Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators. Proc. Natl Acad. Sci. USA 120, e2218896120 (2023).
Xu, Y. et al. COX-2/PGE2 pathway inhibits the ferroptosis induced by cerebral ischemia reperfusion. Mol. Neurobiol. 59, 1619–1631 (2022).
Liu, Y. et al. PGE2 pathway mediates oxidative stress-induced ferroptosis in renal tubular epithelial cells. FEBS J. 290, 533–549 (2023).
Riegman, M. et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol. 22, 1042–1048 (2020).
Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol. 33, 1282–1294 (2023).
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).
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).
von Krusenstiern, A. N. et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat. Chem. Biol. 19, 719–730 (2023).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422 (2018).
Yao, Y. et al. Selenium–GPX4 axis protects follicular helper T cells from ferroptosis. Nat. Immunol. 22, 1127–1139 (2021).
Li, Z. et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat. Chem. Biol. 18, 751–761 (2022).
Zhu, S. et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 77, 2064–2077 (2017).
Wu, Z. et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl Acad. Sci. USA 116, 2996–3005 (2019).
Wu, K. et al. Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. Nat. Cell Biol. 25, 714–725 (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).
Liu, H. et al. Characterization of a patient-derived variant of GPX4 for precision therapy. Nat. Chem. Biol. 18, 91–100 (2022).
Roveri, A. et al. Cardiolipin drives the catalytic activity of GPX4 on membranes: insights from the R152H mutant. Redox Biol. 64, 102806 (2023).
Yant, L. J. et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic. Biol. Med. 34, 496–502 (2003).
Kang, R. et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe 24, 97–108 (2018).
Dai, E. et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat. Commun. 11, 6339 (2020).
Conche, C. et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut 72, 1774–1782 (2023).
Chen, L., Hambright, W. S., Na, R. & Ran, Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J. Biol. Chem. 290, 28097–28106 (2015).
Mayr, L. et al. Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease. Nat. Commun. 11, 1775 (2020).
Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014).
Zheng, J. et al. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 12, 698 (2021).
Forman, H. J., Zhang, H. & Rinna, A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol. Asp. Med. 30, 1–12 (2009).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Deshwal, S. et al. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat. Cell Biol. 25, 246–257 (2023).
Dai, E. et al. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem. Biophys. Res. Commun. 523, 966–971 (2020).
Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).
Kolbrink, B. et al. Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury. Cell Mol. Life Sci. 79, 387 (2022).
Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371–377 (2023).
Mao, C. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586–590 (2021).
Mishima, E. et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E9–E18 (2023).
Mao, C., Liu, X., Yan, Y., Olszewski, K. & Gan, B. Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E19–E23 (2023).
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Liu, L., Wang, M., Gong, N., Tian, P. & Deng, H. Se improves GPX4 expression and SOD activity to alleviate heat-stress-induced ferroptosis-like death in goat mammary epithelial cells. Anim. Cells Syst. 25, 283–295 (2021).
Kapralov, A. A. et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat. Chem. Biol. 16, 278–290 (2020).
Kuang, F., Liu, J., Xie, Y., Tang, D. & Kang, R. MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem. Biol. 28, 765–775 (2021).
Wang, Q. et al. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 12, 426 (2021).
Liu, S. et al. TXNRD1: a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro. Oxid. Med. Cell Longev. 2021, 7674565 (2021).
Rong, Y. et al. DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects. J. Cell. Mol. Med. 25, 2163–2175 (2021).
Lovatt, M. et al. Peroxiredoxin-1 regulates lipid peroxidation in corneal endothelial cells. Redox Biol. 30, 101417 (2020).
Tang, L. et al. TXNDC12 inhibits lipid peroxidation and ferroptosis. iScience 26, 108393 (2023).
Sun, W. Y. et al. Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nat. Chem. Biol. 17, 465–476 (2021).
Chen, D. et al. iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat. Commun. 12, 3644 (2021).
Protchenko, O. et al. Iron chaperone poly rC binding protein 1 protects mouse liver from lipid peroxidation and steatosis. Hepatology 73, 1176–1193 (2021).
Sun, X. et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64, 488–500 (2016).
Komatsu, M. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213–223 (2010).
Sun, X. et al. Activation of the p62–Keap1–NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63, 173–184 (2016).
Anandhan, A. et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci. Adv. 9, eade9585 (2023).
Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
Yang, X. et al. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell Metab. 35, 1474–1490 (2023).
Ou, Y., Wang, S. J., Li, D., Chu, B. & Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl Acad. Sci. USA 113, E6806–E6812 (2016).
Tarangelo, A. et al. p53 Suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 22, 569–575 (2018).
Su, Z. et al. Specific regulation of BACH1 by the hotspot mutant p53R175H reveals a distinct gain-of-function mechanism. Nat. Cancer 4, 564–581 (2023).
Chen, D. et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene 36, 5593–5608 (2017).
Ahola, S. et al. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab. 34, 1875–1891 (2022).
He, F. et al. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. J. Hepatol. 79, 362–377 (2023).
Kalkavan, H. et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356–3374 (2022).
Yang, Z. et al. HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1. Cell Rep. 42, 112945 (2023).
Yao, F. et al. A targetable LIFR–NF-κB–LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat. Commun. 12, 7333 (2021).
Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling. Nature 572, 402–406 (2019).
Yang, W. H. et al. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep. 28, 2501–2508 (2019).
Yi, J., Zhu, J., Wu, J., Thompson, C. B. & Jiang, X. Oncogenic activation of PI3K–AKT–mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc. Natl Acad. Sci. USA 117, 31189–31197 (2020).
Ralhan, I. et al. Autolysosomal exocytosis of lipids protect neurons from ferroptosis. J. Cell Biol. 222, e202207130 (2023).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 9, 1673–1685 (2019).
Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).
Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).
Barayeu, U. et al. Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals. Nat. Chem. Biol. 19, 28–37 (2023).
Sun, J. et al. Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons. J. Clin. Invest. 133, e165228 (2023).
Jia, J. N. et al. Neuroprotective effects of the anti-cancer drug lapatinib against epileptic seizures via suppressing glutathione peroxidase 4-dependent ferroptosis. Front. Pharm. 11, 601572 (2020).
Tonnus, W. et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat. Commun. 12, 4402 (2021).
Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).
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).
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).
Muller, T. et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell. Mol. Life Sci. 74, 3631–3645 (2017).
Feng, H. et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 30, 3411–3423 (2020).
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).
Wen, Q., Liu, J., Kang, R., Zhou, B. & Tang, D. The release and activity of HMGB1 in ferroptosis. Biochem. Biophys. Res. Commun. 510, 278–283 (2019).
Efimova, I. et al. Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J. Immunother. Cancer 8, e001369 (2020).
Yang, L. et al. Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis. Autophagy 19, 1733–1744 (2022).
Liu, J. et al. DCN released from ferroptotic cells ignites AGER-dependent immune responses. Autophagy 18, 2036–2049 (2022).
Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022).
Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577 (2021).
Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012 (2021).
Poznanski, S. M. et al. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab. 33, 1205–1220 (2021).
Han, L. et al. PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity. Biochem. Biophys. Res. Commun. 576, 33–39 (2021).
Ferrer, M. et al. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia. Cell Metab. 35, 1147–1162 (2023).
Zhao, J. et al. Human hematopoietic stem cell vulnerability to ferroptosis. Cell 186, 732–747 (2023).
Song, X. et al. FANCD2 protects against bone marrow injury from ferroptosis. Biochem. Biophys. Res. Commun. 480, 443–449 (2016).
Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A. & Brady, N. R. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2, 517–532 (2015).
Stockwell, B. R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).
Acknowledgements
The authors thank all of the pioneers in the field and our colleagues who contributed to the study of the process and function of ferroptosis. The lead contact D.T. is supported by grants from the US National Institutes of Health (R01CA160417, R01CA229275 and R01GM127791).
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B.R.S. is an inventor on patents and patent applications involving ferroptosis, co-founded (and serves as a consultant to, ProJenX and Exarta Therapeutics, holds equity in Sonata Therapeutics and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. B.G. is an inventor on patent applications involving targeting ferroptosis in cancer therapy and reports personal fees from Guidepoint Global, Cambridge Solutions and NGM Bio. D.I.G. is an employee and shareholder of AstraZeneca. V.G.S. serves as an advisor to, and/or has equity, in Branch Biosciences, Ensoma and Cellarity (all unrelated to the present work). L.G. has/had research contracts with Lytix Biopharma, Promontory and Onxeo; received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. A.I.B. holds shares in Cogstate Ltd, Alterity Ltd and a profit share with Collaborative Medicinal Development LLC, and acts as a paid consultant to Collaborative Medicinal Development LLC. X.J. is an inventor of patents related to autophagy and cell death, and holds equity in, and also consults for, Exarta Therapeutics and Lime Therapeutics. G.K. has research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific cofounder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio; is on the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds; and is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. G.K.’s wife, L. Zitvogel, has held research contracts with GlaxoSmithKline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche; she was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer Ingelheim. The remaining authors declare no competing interests. The funders had no role in the writing of the manuscript.
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Dai, E., Chen, X., Linkermann, A. et al. A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01360-8
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DOI: https://doi.org/10.1038/s41556-024-01360-8
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