Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The chemical basis of ferroptosis

Nature Chemical Biology volume 15, pages 1137–1147 (2019)Cite this article

Subjects

A Publisher Correction to this article was published on 02 January 2020

This article has been updated

Abstract

Lipid peroxidation underlies the mechanism of oxidative cell death now known as ferroptosis. This modality, distinct from other forms of cell death, has been intensely researched in recent years owing to its relevance in both degenerative disease and cancer. The demonstration that it can be modulated by small molecules in multiple pathophysiological contexts offers exciting opportunities for novel pharmacological interventions. Herein, we introduce the salient features of lipid peroxidation, how it can be modulated by small molecules and what principal aspects require urgent investigation by researchers in the field. The central role of non-enzymatic reactions in the execution of ferroptosis will be emphasized, as these processes have hitherto not been generally considered ‘druggable’. Moreover, we provide a critical perspective on the biochemical mechanisms that contribute to cell vulnerability to ferroptosis and discuss how they can be exploited in the design of novel therapeutics.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Lipid peroxidation occurs by a free-radical chain reaction (autoxidation) or enzymatic oxygenation.
Fig. 2: Key contributors to ferroptotic cell death.
Fig. 3: Inhibition of ferroptosis by radical-trapping antioxidants.
Fig. 4: Off-target RTA activity of lipoxygenase inhibitors.
Fig. 5: Key considerations for ferroptosis inhibition by radical-trapping antioxidants.
Fig. 6: Illustration of human diseases in which ferroptosis inhibitors/activators could modulate disease progression.

Change history

  • 02 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Sies, H., Berndt, C. & Jones, D. P. Oxidative stress. Annu. Rev. Biochem. 86, 715–748 (2017).

    CAS  PubMed  Google Scholar 

  2. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    PubMed  PubMed Central  Google Scholar 

  3. Green, D. R. The coming decade of cell death research: five riddles. Cell 177, 1094–1107 (2019).

    CAS  PubMed  Google Scholar 

  4. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). This is the first paper that mentions ferroptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Recknagel, R. O. Carbon tetrachloride hepatotoxicity. Pharmacol. Rev. 19, 145–208 (1967).

    CAS  PubMed  Google Scholar 

  7. Schwarz, K. & Foltz, C. M. Factor 3 activity of selenium compounds. J. Biol. Chem. 233, 245–251 (1958).

    CAS  PubMed  Google Scholar 

  8. Ursini, F., Maiorino, M., Valente, M., Ferri, L. & Gregolin, C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim. Biophys. Acta 710, 197–211 (1982).

    CAS  PubMed  Google Scholar 

  9. 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). This is the first report showing that loss of GPX4 causes a novel form of cell death, now known as ferroptosis.

    CAS  PubMed  Google Scholar 

  10. Sato, H., Tamba, M., Ishii, T. & Bannai, S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274, 11455–11458 (1999).

    CAS  PubMed  Google Scholar 

  11. Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001).

    CAS  PubMed  Google Scholar 

  12. Frank, C. E. Hydrocarbon autoxidation. Chem. Rev. 46, 155–169 (1950).

    CAS  PubMed  Google Scholar 

  13. Criegee, R. Houben-Weyl: Methods of Organic Chemistry, 4th Edn. (Georg Thieme Verlag Stuttgart, 1953).

  14. Yin, H., Xu, L. & Porter, N. A. Free radical lipid peroxidation: mechanisms and analysis. Chem. Rev. 111, 5944–5972 (2011).

    CAS  PubMed  Google Scholar 

  15. Lee, S. H., Oe, T. & Blair, I. A. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 292, 2083–2086 (2001).

    CAS  PubMed  Google Scholar 

  16. Zielinski, Z. A. M. & Pratt, D. A. H-atom abstraction vs. addition: accounting for the diverse product distribution in the autoxidation of cholesterol and its esters. J. Am. Chem. Soc. 131, 3037–3051 (2019).

    Google Scholar 

  17. Xu, L., Korade, Z. & Porter, N. A. Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies. J. Am. Chem. Soc. 132, 2222–2232 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Haeggström, J. Z. & Funk, C. D. Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem. Rev. 111, 5866–5898 (2011).

    PubMed  Google Scholar 

  19. Rouzer, C. A. & Marnett, L. J. Mechanism of free radical oxygenation of polyunsaturated fatty acids by cyclooxygenases. Chem. Rev. 103, 2239–2304 (2003).

    CAS  PubMed  Google Scholar 

  20. Schneider, C., Pratt, D. A., Porter, N. A. & Brash, A. R. Control of oxygenation in lipoxygenase and cyclooxygenase catalysis. Chem. Biol. 14, 473–488 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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). Along with Yang et al. (ref. 21), this work establishes GPX4 as the key ferroptosis regulator both in cancer and in certain pathophysiological contexts.

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017). This paper and that from Dixon et al. (ref. 23) identify and validate ACSL4 as an important downstream player in the ferroptotic process.

    CAS  PubMed  Google Scholar 

  25. Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).

    CAS  PubMed  Google Scholar 

  26. Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl Acad. Sci. USA 113, E4966–E4975 (2016).

    CAS  PubMed  Google Scholar 

  27. 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).

    PubMed  PubMed Central  Google Scholar 

  28. Chu, B. et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat. Cell Biol. 21, 579–591 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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). This paper establishes lipid autoxidation as the driver of ferroptosis and highlights off-target (radical-trapping antioxidant) activity of LOX inhibitors as confounding role of LOX in ferroptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hou, W. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12, 1425–1428 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gao, M. et al. Ferroptosis is an autophagic cell death process. Cell Res. 26, 1021–1032 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kwon, M. Y., Park, E., Lee, S. J. & Chung, S. W. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget 6, 24393–24403 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. Hassannia, B. et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128, 3341–3355 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019).

    CAS  PubMed  Google Scholar 

  35. Sun, X. et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63, 173–184 (2016).

    CAS  PubMed  Google Scholar 

  36. Liang, H. et al. Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J. Biol. Chem. 284, 30836–30844 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Proneth, B. & Conrad, M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 26, 14–24 (2019).

    CAS  PubMed  Google Scholar 

  39. Krainz, T. et al. A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis. ACS Cent. Sci. 2, 653–659 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Griesser, M. et al. The catalytic reaction of nitroxides with peroxyl radicals and its relevance to their cytoprotective properties. J. Am. Chem. Soc. 140, 3798–3808 (2018).

    CAS  PubMed  Google Scholar 

  41. Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Luo, M. et al. miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ. 25, 1457–1472 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gao, M. et al. Role of mitochondria in ferroptosis. Mol. Cell 73, 354–363.e3 (2019).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422.e21 (2018).

    CAS  PubMed  Google Scholar 

  46. Shimada, K. et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 12, 497–503 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Garcia-Bermudez, J. et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118–122 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Frei, B., Kim, M. C. & Ames, B. N. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc. Natl Acad. Sci. USA 87, 4879–4883 (1990).

    CAS  PubMed  Google Scholar 

  49. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature https://doi.org/10.1038/s41586-019-1707-0 (2019).

    CAS  PubMed  Google Scholar 

  50. Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis. Nature https://doi.org/10.1038/s41586-019-1705-2 (2019). This paper and the one by Doll et al. (ref. 49) identify the NADPH–Q 10–FSP1 axis as a complementary system to the cysteine–GSH–GPX4 axis for the control of ferroptosis.

    CAS  PubMed  Google Scholar 

  51. Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432.e9 (2019).

    CAS  PubMed  Google Scholar 

  52. 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).

    PubMed  PubMed Central  Google Scholar 

  53. Boonnoy, P., Jarerattanachat, V., Karttunen, M. & Wong-Ekkabut, J. Bilayer deformation, pores, and micellation induced by oxidized lipids. J. Phys. Chem. Lett. 6, 4884–4888 (2015).

    CAS  PubMed  Google Scholar 

  54. Chen, Y. et al. Quantitative profiling of protein carbonylations in ferroptosis by an aniline-derived probe. J. Am. Chem. Soc. 140, 4712–4720 (2018).

    CAS  PubMed  Google Scholar 

  55. Ingold, K. U. & Pratt, D. A. Advances in radical-trapping antioxidant chemistry in the 21st century: a kinetics and mechanisms perspective. Chem. Rev. 114, 9022–9046 (2014).

    CAS  PubMed  Google Scholar 

  56. Burton, G. W. & Ingold, K. U. Vitamin E: application of the principles of physical organic chemistry to the exploration of its structure and function. Acc. Chem. Res. 19, 194–201 (1986).

    CAS  Google Scholar 

  57. 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). This work establishes that liproxstatins and ferrostatins inhibit ferroptosis as radical-trapping antioxidants, suggesting that lipid autoxidation is the key driver of cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Shah, R., Margison, K. & Pratt, D. A. The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death. ACS Chem. Biol. 12, 2538–2545 (2017).

    CAS  PubMed  Google Scholar 

  59. Farmer, L. A., Haidasz, E. A., Griesser, M. & Pratt, D. A. Phenoxazine: a privileged scaffold for radical-trapping antioxidants. J. Org. Chem. 82, 10523–10536 (2017).

    CAS  PubMed  Google Scholar 

  60. Shah, R., Farmer, L. A., Zilka, O., Van Kessel, A. T. M. & Pratt, D. A. Beyond DPPH: use of fluorescence-enabled inhibited autoxidation to predict oxidative cell death rescue. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2019.09.007 (2019). This paper describes a correlation between small-molecule radical-trapping antioxidant activity in liposomes and antiferroptotic cell potency and establishes that aromatic amines are better antiferroptotic agents than phenols because of reduced hydrogen bonding with phospholipid headgroups.

    PubMed  Google Scholar 

  61. Poon, J. F. & Pratt, D. A. Recent insights on hydrogen atom transfer in the inhibition of hydrocarbon autoxidation. Acc. Chem. Res. 51, 1996–2005 (2018).

    CAS  PubMed  Google Scholar 

  62. Harrison, K. A., Haidasz, E. A., Griesser, M. & Pratt, D. A. Inhibition of hydrocarbon autoxidation by nitroxide-catalyzed cross-dismutation of hydroperoxyl and alkylperoxyl radicals. Chem. Sci. 9, 6068–6079 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ingold, K. U., Bowry, V. W., Stocker, R. & Walling, C. Autoxidation of lipids and antioxidation by alpha-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size as exemplified by oxidation of human low density lipoprotein. Proc. Natl Acad. Sci. USA 90, 45–49 (1993).

    CAS  PubMed  Google Scholar 

  64. Muchalski, H., Levonyak, A. J., Xu, L., Ingold, K. U. & Porter, N. A. Competition H(D) kinetic isotope effects in the autoxidation of hydrocarbons. J. Am. Chem. Soc. 137, 94–97 (2015).

    CAS  PubMed  Google Scholar 

  65. Firsov, A. M. et al. Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers. FEBS J. 286, 2099–2117 (2019).

    CAS  PubMed  Google Scholar 

  66. Gao, J. et al. Selenium-encoded isotopic signature targeted profiling. ACS Cent. Sci. 4, 960–970 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Eaton, J. K. et al. Targeting a therapy-resistant cancer cell state using masked electrophiles as GPX4 inhibitors. Preprint at bioRxiv https://doi.org/10.1101/376764 (2018).

  68. Conrad, M., Angeli, J. P., Vandenabeele, P. & Stockwell, B. R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 15, 348–366 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Shen, Z. et al. Emerging strategies of cancer therapy based on ferroptosis. Adv. Mater. 30, e1704007 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Kim, S. E. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat. Nanotechnol. 11, 977–985 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14, 507–515 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Beatty, A. et al. Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer. Preprint at bioRxiv https://doi.org/10.1101/556084 (2019).

  73. Conrad, M. et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 32, 602–619 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).

    CAS  PubMed  Google Scholar 

  75. Tuo, Q. Z. et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol. Psychiatry 22, 1520–1530 (2017).

    CAS  PubMed  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Skouta, R. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lőrincz, T., Jemnitz, K., Kardon, T., Mandl, J. & Szarka, A. Ferroptosis is involved in acetaminophen induced cell death. Pathol. Oncol. Res. 21, 1115–1121 (2015).

    PubMed  Google Scholar 

  80. Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. J. Am. Med. Assoc. 297, 842–857 (2007).

    CAS  Google Scholar 

  81. Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017). This paper and that by Viswanathan et al. (ref 81) demonstrate that therapy-resistant cells and cells undergoing epithelial mesenchymal transition acquire a unique dependency on the GPX4–GSH–cysteine axis, and are therefore vulnerable to ferroptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Friedmann Angeli, J. P., Krysko, D. V. & Conrad, M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat. Rev. Cancer 19, 405–414 (2019).

    CAS  PubMed  Google Scholar 

  85. Miess, H. et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene 37, 5435–5450 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Alvarez, S. W. et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551, 639–643 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Basuli, D. et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36, 4089–4099 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Sato, H. et al. Redox imbalance in cystine/glutamate transporter-deficient mice. J. Biol. Chem. 280, 37423–37429 (2005).

    CAS  PubMed  Google Scholar 

  90. Conrad, M. & Sato, H. The oxidative stress-inducible cystine/glutamate antiporter, system xc - : cystine supplier and beyond. Amino Acids 42, 231–246 (2012).

    CAS  PubMed  Google Scholar 

  91. Liu, T., Jiang, L., Tavana, O. & Gu, W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 79, 1913–1924 (2019).

    CAS  PubMed  Google Scholar 

  92. Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Sato, H., Fujiwara, K., Sagara, J. & Bannai, S. Induction of cystine transport activity in mouse peritoneal macrophages by bacterial lipopolysaccharide. Biochem. J. 310, 547–551 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

  96. Lim, J. K. M. et al. Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc. Natl Acad. Sci. USA 116, 9433–9442 (2019).

    CAS  PubMed  Google Scholar 

  97. 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).

    CAS  PubMed  Google Scholar 

  98. 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).

    CAS  PubMed  Google Scholar 

  99. Weïwer, M. et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg. Med. Chem. Lett. 22, 1822–1826 (2012).

    PubMed  Google Scholar 

  100. Latchoumycandane, C., Marathe, G. K., Zhang, R. & McIntyre, T. M. Oxidatively truncated phospholipids are required agents of tumor necrosis factor α (TNFα)-induced apoptosis. J. Biol. Chem. 287, 17693–17705 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Marcus Conrad, Derek A. Pratt.

Authors and Affiliations

  1. Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany

    Marcus Conrad

  2. Department of Chemistry and Biomolecular Science, University of Ottawa, Ottawa, Canada

    Derek A. Pratt

Authors
  1. Marcus Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Derek A. Pratt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Marcus Conrad or Derek A. Pratt.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conrad, M., Pratt, D.A. The chemical basis of ferroptosis. Nat Chem Biol 15, 1137–1147 (2019). https://doi.org/10.1038/s41589-019-0408-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-019-0408-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer