Abstract
Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Galy, B., Conrad, M. & Muckenthaler, M. Mechanisms controlling cellular and systemic iron homeostasis.Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-023-00648-1 (2023).
Conrad, M. & Pratt, D. A. The chemical basis of ferroptosis. Nat. Chem. Biol. 15, 1137–1147 (2019).
Ursini, F. & Maiorino, M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic. Biol. Med. 152, 175–185 (2020).
Conrad, M. et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 32, 602–619 (2018).
Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).
Stockwell, B. R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).
Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis.Curr. Biol. 33, 1282–1294.e5 (2023).
Dixon, S. J. & Pratt, D. A. Ferroptosis: a flexible constellation of related biochemical mechanisms. Mol. Cell 83, 1030–1042 (2023).
Green, D. R. The coming decade of cell death research: five riddles. Cell 177, 1094–1107 (2019).
Kayagaki, N. et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591, 131–136 (2021).
Dondelinger, Y. et al. NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis. Cell Death Dis. 14, 755 (2023).
Pope, L. E. & Dixon, S. J. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 33, 1077–1087 (2023).
Liang, D., Minikes, A. M. & Jiang, X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol. Cell 82, 2215–2227 (2022).
Li, Z., Lange, M., Dixon, S. J. & Olzmann, J. A. Lipid quality control and ferroptosis: from concept to mechanism. Annu. Rev. Biochem. https://doi.org/10.1146/annurev-biochem-052521-033527 (2023).
Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641.e6 (2017).
Shah, R., Shchepinov, M. S. & Pratt, D. A. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent. Sci. 4, 387–396 (2018).
Zilka, O. et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent. Sci. 3, 232–243 (2017).
Anthonymuthu, T. S. et al. Resolving the paradox of ferroptotic cell death: ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis. Redox Biol. 38, 101744 (2021).
Tyurina, Y. Y. et al. Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo. Redox Biol. 61, 102650 (2023).
Kathman, S. G., Boshart, J., Jing, H. & Cravatt, B. F. Blockade of the lysophosphatidylserine lipase ABHD12 potentiates ferroptosis in cancer cells. ACS Chem. Biol. 15, 871–877 (2020).
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Phadnis, V. V. et al. MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis. Cell Rep. 42, 113023 (2023).
Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).
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).
Magtanong, L. et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem. Biol. 29, 1409–1418.e6 (2022).
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432.e9 (2019).
von Krusenstiern, A. N. et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat. Chem. Biol. 19, 719–730 (2023).
Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).
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).
Riegman, M. et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol. 22, 1042–1048 (2020).
Agmon, E., Solon, J., Bassereau, P. & Stockwell, B. R. Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci. Rep. 8, 5155 (2018).
Roveri, A., Maiorino, M., Nisii, C. & Ursini, F. Purification and characterization of phospholipid hydroperoxide glutathione peroxidase from rat testis mitochondrial membranes. Biochim. Biophys. Acta 1208, 211–221 (1994).
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).
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).
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).
Labrecque, C. L. & Fuglestad, B. Electrostatic drivers of GPx4 interactions with membrane, lipids, and DNA. Biochemistry 60, 2761–2772 (2021).
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).
Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).
Lv, Y. et al. Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat. Commun. 14, 5933 (2023).
Soula, M. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 16, 1351–1360 (2020).
Jakaria, M., Belaidi, A. A., Bush, A. I. & Ayton, S. Vitamin A metabolites inhibit ferroptosis. Biomed. Pharmacother. 164, 114930 (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).
Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300.e16 (2017).
Ruhl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018).
Yang, W. H. et al. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep. 28, 2501–2508.e4 (2019).
Poursaitidis, I. et al. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep. 18, 2547–2556 (2017).
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).
Guan, Y. et al. A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis. Nat. Commun. 12, 5078 (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.e5 (2021).
Lin, Z. et al. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. Nat. Commun. 13, 7965 (2022).
Cao, J. Y. et al. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep. 26, 1544–1556.e8 (2019).
Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014).
Armenta, D. A. et al. Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein. Cell Chem. Biol. 29, 1588–1600.e7 (2022).
Kobayashi, S. et al. Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides. Free Radic. Biol. Med. 174, 12–27 (2021).
Hayashima, K. & Katoh, H. Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis. J. Biol. Chem. 298, 101703 (2022).
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).
Li, Z. et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat. Chem. Biol. 18, 751–761 (2022).
Greenough, M. A. et al. Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations. Cell Death Differ. 29, 2123–2136 (2022).
Alborzinia, H. et al. LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma. EMBO Mol. Med. 15, e18014 (2023).
Carlisle, A. E. et al. Selenium detoxification is required for cancer-cell survival. Nat. Metab. 2, 603–611 (2020).
Howard, M. T., Carlson, B. A., Anderson, C. B. & Hatfield, D. L. Translational redefinition of UGA codons is regulated by selenium availability. J. Biol. Chem. 288, 19401–19413 (2013).
Harris, I. S. et al. Deubiquitinases maintain protein homeostasis and survival of cancer cells upon glutathione depletion. Cell Metab. 29, 1166–1181.e6 (2019).
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 (2022).
Wu, Z. et al. Hydropersulfides inhibit lipid peroxidation and protect cells from ferroptosis. J. Am. Chem. Soc. 144, 15825–15837 (2022).
Kang, Y. P. et al. Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab. 33, 174–189.e7 (2021).
Chen, L. et al. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat. Metab. 1, 404–415 (2019).
Shimada, K., Hayano, M., Pagano, N. C. & Stockwell, B. R. Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem. Biol. 23, 225–235 (2016).
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.e10 (2021).
Zou, Y. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol. 16, 302–309 (2020).
Ding, C. C. et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab. 2, 270–277 (2020).
Nguyen, K. T. et al. The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis. Nat. Cell Biol. 24, 1239–1251 (2022).
Yagoda, N. et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).
Gaschler, M. M. et al. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem. Biol. 13, 1013–1020 (2018).
Bogacz, M. & Krauth-Siegel, R. L. Tryparedoxin peroxidase-deficiency commits trypanosomes to ferroptosis-type cell death. eLife 7, e37503 (2018).
Guo, Y. et al. Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction. Nat. Chem. Biol. 19, 468–477 (2023).
Ahola, S. et al. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab. 34, 1875–1891.e7 (2022).
Guerra, R. M. & Pagliarini, D. J. Coenzyme Q biochemistry and biosynthesis. Trends Biochem. Sci. 48, 463–476 (2023).
Deshwal, S. et al. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat. Cell Biol. 25, 246–257 (2023).
Blomme, A. et al. 2,4-Dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nat. Commun. 11, 2508 (2020).
Nassar, Z. D. et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. eLife 9, e54166 (2020).
Gao, M. et al. Role of mitochondria in ferroptosis. Mol. Cell 73, 354–363.e3 (2019).
Conlon, M. et al. A compendium of kinetic modulatory profiles identifies ferroptosis regulators. Nat. Chem. Biol. 17, 665–674 (2021).
Zhang, T. et al. ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat. Cancer 3, 75–89 (2022).
Alvarez, S. W. et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551, 639–643 (2017).
Kalkavan, H. et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356–3374.e22 (2022).
Tarangelo, A. et al. Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity. Life Sci. Alliance 5, e202101157 (2022).
Wu, S. et al. A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. Proc. Natl Acad. Sci. USA 119, e2121987119 (2022).
Yang, C. et al. De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat. Cell Biol. 25, 836–847 (2023).
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.e6 (2022).
Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl Acad. Sci. USA 113, E4966–E4975 (2016).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Mann, J. et al. Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2023.10.012 (2023).
Perez, M. A., Magtanong, L., Dixon, S. J. & Watts, J. L. Dietary lipids induce ferroptosis in Caenorhabditis elegans and human cancer cells. Dev. Cell 54, 447–454.e4 (2020).
Lee, J. Y. et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc. Natl Acad. Sci. USA 117, 32433–32442 (2020).
Yamane, D. et al. FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication. Cell Chem. Biol. 29, 799–810.e4 (2022).
Xin, S. et al. MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling. Cell Death Differ. 29, 670–686 (2022).
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).
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Bartolacci, C. et al. Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer. Nat. Commun. 13, 4327 (2022).
Radif, Y. et al. The endogenous subcellular localisations of the long chain fatty acid-activating enzymes ACSL3 and ACSL4 in sarcoma and breast cancer cells. Mol. Cell Biochem. 448, 275–286 (2018).
Kuch, E. M. et al. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. Biochim. Biophys. Acta 1841, 227–239 (2014).
Poppelreuther, M. et al. The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake. J. Lipid Res. 53, 888–900 (2012).
Zhu, X. G. et al. CHP1 regulates compartmentalized glycerolipid synthesis by activating GPAT4. Mol. Cell 74, 45–58.e7 (2019).
Beharier, O. et al. PLA2G6 guards placental trophoblasts against ferroptotic injury. Proc. Natl Acad. Sci. USA 117, 27319–27328 (2020).
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).
Reed, A. et al. LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from ferroptosis. ACS Chem. Biol. 17, 1607–1618 (2022).
Liang, D. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186, 2748–2794.e22 (2023).
Rodencal, J. et al. Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2023.10.011 (2023).
Zhao, Y. et al. Identification and characterization of a major liver lysophosphatidylcholine acyltransferase. J. Biol. Chem. 283, 8258–8265 (2008).
Mishra, R. S., Carnevale, K. A. & Cathcart, M. K. iPLA2β: front and center in human monocyte chemotaxis to MCP-1. J. Exp. Med. 205, 347–359 (2008).
Friedmann Angeli, J. P. et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Preprint at Res. Sq. https://doi.org/10.21203/rs.3.rs-943221/v1 (2021).
Yamada, N. et al. DHCR7 as a novel regulator of ferroptosis in hepatocytes. Preprint at bioRxiv https://doi.org/10.1101/2022.06.15.496212 (2022).
Garcia-Bermudez, J. et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118–122 (2019).
Schumacher, M. M. & DeBose-Boyd, R. A. Posttranslational regulation of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol. Annu. Rev. Biochem. 90, 659–679 (2021).
Conrad, M. & Proneth, B. Selenium: tracing another essential element of ferroptotic cell death. Cell Chem. Biol. 27, 409–419 (2020).
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).
Vangala, J. R., Sotzny, F., Kruger, E., Deshaies, R. J. & Radhakrishnan, S. K. Nrf1 can be processed and activated in a proteasome-independent manner. Curr. Biol. 26, R834–R835 (2016).
Tomlin, F. M. et al. Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity. ACS Cent. Sci. 3, 1143–1155 (2017).
Chavarria, C. et al. ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation. iScience 26, 107777 (2023).
Dirac-Svejstrup, A. B. et al. DDI2 Is a ubiquitin-directed endoprotease responsible for cleavage of transcription factor NRF1. Mol. Cell 79, 332–341.e7 (2020).
Forcina, G. C. et al. Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proc. Natl Acad. Sci. USA 119, e2118646119 (2022).
Kotschi, S. et al. NFE2L1-mediated proteasome function protects from ferroptosis. Mol. Metab. 57, 101436 (2022).
Song, W., Zhang, W., Yue, L. & Lin, W. Revealing the effects of endoplasmic reticulum stress on ferroptosis by two-channel real-time imaging of pH and viscosity. Anal. Chem. 94, 6557–6565 (2022).
Danielli, M., Perne, L., Jarc Jovicic, E. & Petan, T. Lipid droplets and polyunsaturated fatty acid trafficking: balancing life and death. Front. Cell Dev. Biol. 11, 1104725 (2023).
Olzmann, J. A. & Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137–155 (2019).
Dierge, E. et al. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 33, 1701–1715.e5 (2021).
Minami, J. K. et al. CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis. Cancer Cell 41, 1048–1060.e9 (2023).
Lee, H. et al. Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance. Nat. Commun. 15, 79 (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).
Ferrada, L., Barahona, M. J., Vera, M., Stockwell, B. R. & Nualart, F. Dehydroascorbic acid sensitizes cancer cells to system xc- inhibition-induced ferroptosis by promoting lipid droplet peroxidation. Cell Death Dis. 14, 637 (2023).
Mohammadyani, D. et al. Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: mass spectrometry and coarse-grained simulations. Free Radic. Biol. Med. 76, 53–60 (2014).
Perez, M. A. et al. Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity. PLoS Genet. 18, e1010436 (2022).
Alborzinia, H. et al. Golgi stress mediates redox imbalance and ferroptosis in human cells. Commun. Biol. 1, 210 (2018).
Huang, Y. et al. UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult. Cell Biosci. 12, 42 (2022).
Nakagawa, K. et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468, 117–121 (2010).
Rost, S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537–541 (2004).
Jin, D. Y. et al. A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. Nat. Commun. 14, 828 (2023).
Yang, X. et al. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism.Cell Metab. 35, 1474–1490.e8 (2023).
Mugoni, V. et al. Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 152, 504–518 (2013).
Jo, Y. & DeBose-Boyd, R. A. Post-translational regulation of HMG CoA reductase. Cold Spring Harb. Perspect. Biol. 14, a041253 (2022).
Torii, S. et al. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem. J. 473, 769–777 (2016).
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).
Gryzik, M., Asperti, M., Denardo, A., Arosio, P. & Poli, M. NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells. Biochim. Biophys. Acta Mol. Cell Res. 1868, 118913 (2021).
Anandhan, A. et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci. Adv. 9, eade9585 (2023).
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).
Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).
Swanda, R. V. et al. Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response. Mol. Cell 10, 3347–3359.e9 (2023).
Zhang, Y. et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun. 12, 1589 (2021).
Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).
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).
Vaca, C. E. & Harms-Ringdahl, M. Nuclear membrane lipid peroxidation products bind to nuclear macromolecules. Arch. Biochem. Biophys. 269, 548–554 (1989).
Zhang, Y. et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol. 26, 623–633.e9 (2019).
Tarangelo, A. et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 22, 569–575 (2018).
Muller, F. et al. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ. 30, 442–456 (2023).
Koppula, P. et al. A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun. 13, 2206 (2022).
Takahashi, N. et al. 3D culture models with CRISPR screens reveal hyperactive NRF2 as a prerequisite for spheroid formation via regulation of proliferation and ferroptosis. Mol. Cell 80, 828–844.e6 (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.e5 (2021).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Wang, L. et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–. Cell Death Differ. 27, 662–675 (2020).
Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402–406 (2019).
Venkatesh, D. et al. MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes Dev. 34, 526–543 (2020).
Liu, J. et al. NUPR1 is a critical repressor of ferroptosis. Nat. Commun. 12, 647 (2021).
Alborzinia, H. et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat. Cancer 3, 471–485 (2022).
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).
Zhang, Y., Koppula, P. & Gan, B. Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1. Cell Cycle 18, 773–783 (2019).
Valente, L. J. et al. p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen. J. Cell Biol. 219, e201908212 (2020).
Wohlhieter, C. A. et al. Concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence in lung cancer. Cell Rep. 33, 108444 (2020).
Zhao, Y. et al. HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep. 33, 108487 (2020).
Tesfay, L. et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 79, 5355–5366 (2019).
Lee, H. et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol. 22, 225–234 (2020).
Acoba, M. G., Senoo, N. & Claypool, S. M. Phospholipid ebb and flow makes mitochondria go. J. Cell Biol. 219, e202023131 (2020).
Barger, S. R., Penfield, L. & Bahmanyar, S. Coupling lipid synthesis with nuclear envelope remodeling. Trends Biochem. Sci. 47, 52–65 (2022).
Zhang, H. L. et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol. 24, 88–98 (2022).
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.e4 (2023).
Cui, S. et al. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases. Mol. Cell 83, 3931–3939.e5 (2023).
Rodencal, J. & Dixon, S. J. Positive feedback amplifies ferroptosis. Nat. Cell Biol. 24, 4–5 (2022).
Brown, C. W. et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev. Cell 51, 575–586.e4 (2019).
Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703.e10 (2023).
Feng, H. et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 30, 3411–3423.e7 (2020).
Jia, M. et al. Redox homeostasis maintained by GPX4 facilitates STING activation. Nat. Immunol. 21, 727–735 (2020).
Xie, Y. et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 20, 1692–1704 (2017).
Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).
Tian, R. et al. Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat. Neurosci. 24, 1020–1034 (2021).
Ryan, S. K. et al. Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nat. Neurosci. 26, 12–26 (2023).
Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).
Brown, C. W., Amante, J. J. & Mercurio, A. M. Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. J. Biol. Chem. 293, 12741–12748 (2018).
Dar, H. H. et al. Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium. J. Clin. Invest. 128, 4639–4653 (2018).
Belavgeni, A. et al. vPIF-1 is an insulin-like antiferroptotic viral peptide. Proc. Natl Acad. Sci. USA 120, e2300320120 (2023).
Jin, J. et al. Machine learning classifies ferroptosis and apoptosis cell death modalities with TfR1 immunostaining. ACS Chem. Biol. 17, 654–660 (2022).
Shimada, K. et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 12, 497–503 (2016).
Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L. & Coyle, J. T. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2, 1547–1558 (1989).
Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001).
Ratan, R. R., Murphy, T. H. & Baraban, J. M. Macromolecular synthesis inhibitors prevent oxidative stress-induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione. J. Neurosci. 14, 4385–4392 (1994).
Wiernicki, B. et al. Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis. Cell Death Dis. 11, 922 (2020).
Skouta, R. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556 (2014).
Poon, J. F., Zilka, O. & Pratt, D. A. Potent ferroptosis inhibitors can catalyze the cross-dismutation of phospholipid-derived peroxyl radicals and hydroperoxyl radicals. J. Am. Chem. Soc. 142, 14331–14342 (2020).
Hadian, K. & Stockwell, B. R. A roadmap to creating ferroptosis-based medicines. Nat. Chem. Biol. 17, 1113–1116 (2021).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Hendricks, J. M. et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. 30, 1090–1103.e7 (2023).
Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371–377 (2023).
Farmer, L. A. et al. Intrinsic and extrinsic limitations to the design and optimization of inhibitors of lipid peroxidation and associated cell death. J. Am. Chem. Soc. 144, 14706–14721 (2022).
Jelinek, A. et al. Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic. Biol. Med. 117, 45–57 (2018).
Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019).
Merkel, M. et al. Mitochondrial reactive oxygen species formation determines ACSL4/LPCAT2-mediated ferroptosis. Antioxidants 12, 1590 (2023).
Doulias, P. T., Christoforidis, S., Brunk, U. T. & Galaris, D. Endosomal and lysosomal effects of desferrioxamine: protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest. Free Radic. Biol. Med. 35, 719–728 (2003).
Kurz, T., Gustafsson, B. & Brunk, U. T. Intralysosomal iron chelation protects against oxidative stress-induced cellular damage. FEBS J. 273, 3106–3117 (2006).
Fang, Y. et al. Inhibiting ferroptosis through disrupting the NCOA4-FTH1 interaction: a new mechanism of action. ACS Cent. Sci. 7, 980–989 (2021).
Xu, Y., Li, X., Cheng, Y., Yang, M. & Wang, R. Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia-reperfusion. FASEB J. 34, 16262–16275 (2020).
Li, Y. et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 26, 2284–2299 (2019).
Ide, S. et al. Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair. Cell Rep. 41, 111610 (2022).
Yan, H. et al. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations. Redox Biol. 62, 102699 (2023).
Jennis, M. et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 30, 918–930 (2016).
Leu, J. I., Murphy, M. E. & George, D. L. Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53. Proc. Natl Acad. Sci. USA 117, 26804–26811 (2020).
Acknowledgements
The authors thank L. Magtanong, D. Pratt and members of the Dixon and Olzmann labs for discussion and comments on the manuscript. This work is supported by the National Institutes of Health (R01GM122923 to S.J.D. and R01GM112948 to J.A.O.) and the American Cancer Society (RSG-21-017-01 to S.J.D. and RSG-19-192-01 to J.A.O.). J.A.O. is a Chan Zuckerberg Biohub Investigator and is also supported by a Bakar Fellows Spark Award.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding authors
Ethics declarations
Competing interests
S.J.D. is a co-founder of Prothegen and a member of the scientific advisory board for Hillstream BioPharma. S.J.D. holds patents related to ferroptosis. J.A.O. is a member of the scientific advisory board for Vicinitas Therapeutics and holds patents related to ferroptosis.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks Fudi Wang, José Pedro Friedmann Angeli and Qitao Ran for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Caveolae
-
Small invaginations of the plasma membrane enriched for certain lipids and proteins.
- Endocytosis
-
The process of taking up materials from outside the cells into intracellular vesicles called endosomes. Endosomes can then transport materials within the cell to other compartments such as the lysosome.
- Ether lipid
-
A class of phospholipid where one of the two fatty acyl chains is bound to the glycerol backbone by an ether bond rather than the more common ester bond. Ether lipids may contribute importantly to the execution of ferroptosis in some cells.
- Ferritinophagy
-
The catabolism of iron-laden ferritin nanocages in the autophagolysosome to release free iron atoms.
- Fe–S clusters
-
Iron–sulfur clusters are essential enzyme cofactors. Several different configurations of iron and sulfur atoms yield distinct types of clusters.
- Integrated stress response
-
A gene expression programme that can help the cell respond to a shortage of individual amino acids by increasing the expression of membrane transporters and other metabolic enzymes that restore homeostasis.
- Lipolysis
-
The enzymatic breakdown of triacylglycerol to glycerol and free fatty acids mediated by a series of lipases recruited to the lipid droplet surface.
- Lipophagy
-
The breakdown of the lipid droplet, or a portion of the lipid droplet, through its delivery to the lysosome by a selective autophagic pathway.
- Membrane contact sites
-
Regions of close proximity between two organelles that are often stabilized by protein tethers. These sites typically function as sites for the exchange of lipids and metabolites.
- Monounsaturated fatty acids
-
(MUFAs). Fatty acid molecules that contain a single carbon–carbon double bond.
- Necroptosis and pyroptosis
-
Two forms of non-apoptotic cell death that are biochemically distinct from each other and from ferroptosis.
- Polyunsaturated fatty acid
-
(PUFA). Fatty acid molecule that contains multiple carbon–carbon double bonds, making it more sensitive to oxidative damage.
- Reactive oxygen species
-
(ROS). An umbrella term for a number of small oxygen radicals and species that contain oxygen and which can easily form radical-containing species. Oxygen radicals that may initiate lipid peroxidation, leading to ferroptosis, include the hydroperoxyl radical (the conjugate acid of superoxide) and the hydroxyl radical, which itself can be formed from the Fenton reaction between hydrogen peroxide and iron.
- Selenoprotein
-
One of a small number of proteins in mammalian cells that incorporate the unusual selenium-containing amino acid selenocysteine. Typically, these proteins are involved in some aspect of redox regulation in the cell.
- Stimulator of interferon genes
-
(STING). A protein that can sense DNA in the cytosol and orchestrate a downstream immune response by binding to other signalling proteins.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dixon, S.J., Olzmann, J.A. The cell biology of ferroptosis. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00703-5
Accepted:
Published:
DOI: https://doi.org/10.1038/s41580-024-00703-5