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Cited by 1,596Ferroptosis and cancer prognosisIron Metabolism and DisordersCell death mechanisms and regulation

The Cell Biology of Ferroptosis

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Dixon, Scott J., Olzmann, James A.·2024·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-024-00703-5PMC PMC12187608
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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.

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  • Ferroptosis is an iron-dependent RCD pathway characterized by lipid peroxidation and downregulation of antioxidant defense.

    “Ferroptosis represents an iron-dependent RCD pathway characterized by lipid peroxidation and downregulation of the antioxidant defense of cells [39,40,41].”

    From Role of Regulated Cell Death Pathways in Snakebite Envenomation: Mechanisms, Crosstalk, and Therapeutic Opportunities (2026) · cites this paper as [40]

    The Introduction identifies ferroptosis as an iron-dependent cell-death mechanism defined by membrane lipid peroxidation. Its ‘Suppression of membrane lipid peroxidation’ section explains that antioxidant systems prevent ferroptosis and can be inhibited to induce it, but does not establish downregulation of antioxidant defenses as a defining feature of every ferroptotic pathway. No page numbers are provided in our copy. (LLM, conf=0.85)

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  1. [1]Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060– 1072 (2012). 22632970 PMC3367386
  2. [2]Galy B, Conrad M & Muckenthaler M Mechanisms controlling cellular and systemic iron homeostasis. Nat. Rev. Mol. Cell Biol 10.1038/s41580-023-00648-1 (2023). 37783783 · DOI
  3. [3]Conrad M & Pratt DA The chemical basis of ferroptosis. Nat. Chem. Biol 15, 1137– 1147 (2019). 31740834
  4. [5]Conrad M Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32, 602– 619 (2018). 29802123 PMC6004068
  5. [6]Jiang L Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57– 62 (2015). 25799988 PMC4455927
  6. [7]Zhang Y BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol 20, 1181– 1192 (2018). 30202049 PMC6170713
  7. [8]Stockwell BR Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401– 2421 (2022). 35803244 PMC9273022
  8. [9]Hirata Y Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol 33, 1282– 1294.e5 (2023). 36898371
  9. [10]Dixon SJ & Pratt DA Ferroptosis: a flexible constellation of related biochemical mechanisms. Mol. Cell 83, 1030– 1042 (2023). 36977413 PMC10081971
  10. [11]Green DR The coming decade of cell death research: five riddles. Cell 177, 1094– 1107 (2019). 31100266 PMC6534278
  11. [12]Kayagaki N NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591, 131– 136 (2021). 33472215
  12. [13]Dondelinger Y NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis. Cell Death Dis 14, 755 (2023). 37980412 PMC10657445
  13. [14]Pope LE & Dixon SJ Regulation of ferroptosis by lipid metabolism. Trends Cell Biol 33, 1077– 1087 (2023). 37407304 PMC10733748
  14. [15]Liang D, Minikes AM & Jiang X Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol. Cell 82, 2215– 2227 (2022). 35390277 PMC9233073
  15. [16]Li Z, Lange M, Dixon SJ & Olzmann JA Lipid quality control and ferroptosis: from concept to mechanism. Annu. Rev. Biochem 10.1146/annurev-biochem-052521-033527 (2023). PMC11091000 37963395 · DOI
  16. [17]Wenzel SE PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628– 641.e6 (2017). 29053969 PMC5683852
  17. [18]Shah R, Shchepinov MS & Pratt DA Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent. Sci 4, 387– 396 (2018). 29632885 PMC5879472
  18. [19]Zilka O 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). 28386601 PMC5364454
  19. [20]Anthonymuthu TS 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). 33126055 PMC7596334
  20. [21]Tyurina YY Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo. Redox Biol 61, 102650 (2023). 36870109 PMC9996109
  21. [22]Kathman SG, Boshart J, Jing H & Cravatt BF Blockade of the lysophosphatidylserine lipase ABHD12 potentiates ferroptosis in cancer cells. ACS Chem. Biol 15, 871– 877 (2020). 32195565 PMC7386317
  22. [23]Kraft VAN GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci 6, 41– 53 (2020). 31989025 PMC6978838
  23. [24]Phadnis VV MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis. Cell Rep 42, 113023 (2023). 37691145 PMC10591818
  24. [25]Zou Y Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603– 608 (2020). 32939090 PMC8051864
  25. [26]Reed A, Ware T, Li H, Fernando Bazan J & Cravatt BF TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids. Nat. Chem. Biol 19, 378– 388 (2023). 36782012 PMC10362496
  26. [27]Magtanong L Context-dependent regulation of ferroptosis sensitivity. Cell Chem. Biol 29, 1409– 1418.e6 (2022). 35809566 PMC9481678
  27. [28]Magtanong L Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol 26, 420– 432.e9 (2019). 30686757 PMC6430697
  28. [29]von Krusenstiern AN Identification of essential sites of lipid peroxidation in ferroptosis. Nat. Chem. Biol 19, 719– 730 (2023). 36747055 PMC10238648
  29. [30]Kagan VE Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol 13, 81– 90 (2017). 27842066 PMC5506843
  30. [31]Pedrera L Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ 28, 1644– 1657 (2021). 33335287 PMC8167089
  31. [32]Riegman M Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol 22, 1042– 1048 (2020). 32868903 PMC7644276
  32. [33]Agmon E, Solon J, Bassereau P & Stockwell BR Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci. Rep 8, 5155 (2018). 29581451 PMC5979948
  33. [34]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). 7524677
  34. [36]Friedmann Angeli JP Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol 16, 1180– 1191 (2014). 25402683 PMC4894846
  35. [37]Mao C DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586– 590 (2021). 33981038 PMC8895686
  36. [38]Mishima E DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E9– E18 (2023). 37407687
  37. [39]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). 37407682
  38. [40]Labrecque CL & Fuglestad B Electrostatic drivers of GPx4 interactions with membrane, lipids, and DNA. Biochemistry 60, 2761– 2772 (2021). 34492183
  39. [41]Bersuker K The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688– 692 (2019). 31634900 PMC6883167
  40. [42]Doll S FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693– 698 (2019). 31634899
  41. [43]Mishima E A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778– 783 (2022). 35922516 PMC9402432
  42. [44]Lv Y Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat. Commun 14, 5933 (2023). 37739943 PMC10516921
  43. [45]Soula M Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol 16, 1351– 1360 (2020). 32778843 PMC8299533
  44. [46]Jakaria M, Belaidi AA, Bush AI & Ayton S Vitamin A metabolites inhibit ferroptosis. Biomed. Pharmacother 164, 114930 (2023). 37236031
  45. [47]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). 31761326 PMC6957708
  46. [48]Gong YN ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286– 300.e16 (2017). 28388412 PMC5443414
  47. [49]Ruhl S ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956– 960 (2018). 30467171
  48. [50]Yang WH The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep 28, 2501– 2508.e4 (2019). 31484063 PMC10440760
  49. [51]Poursaitidis I Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep 18, 2547– 2556 (2017). 28297659 PMC5368412
  50. [53]Gao M, Monian P, Quadri N, Ramasamy R & Jiang X Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298– 308 (2015). 26166707 PMC4506736
  51. [54]Guan Y A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis. Nat. Commun 12, 5078 (2021). 34426578 PMC8382756
  52. [55]Ma X CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab 33, 1001– 1012.e5 (2021). 33691090 PMC8102368
  53. [56]Lin Z The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. Nat. Commun 13, 7965 (2022). 36575162 PMC9794750
  54. [57]Cao JY A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep 26, 1544– 1556.e8 (2019). 30726737 PMC6424331
  55. [58]Dixon SJ Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014). 24844246 PMC4054777
  56. [59]Armenta DA Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein. Cell Chem. Biol 29, 1588– 1600.e7 (2022). 36306785 PMC9762237
  57. [60]Kobayashi S Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides. Free Radic. Biol. Med 174, 12– 27 (2021). 34324979
  58. [61]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). 35148992 PMC8897698
  59. [62]Zhang L 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). PMC9651629 35867762
  60. [65]Alborzinia H LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma. EMBO Mol. Med 15, e18014 (2023). 37435859 PMC10405063
  61. [66]Carlisle AE Selenium detoxification is required for cancer-cell survival. Nat. Metab 2, 603– 611 (2020). 32694795 PMC7455022
  62. [67]Howard MT, Carlson BA, Anderson CB & Hatfield DL Translational redefinition of UGA codons is regulated by selenium availability. J. Biol. Chem 288, 19401– 19413 (2013). 23696641 PMC3707644
  63. [68]Harris IS Deubiquitinases maintain protein homeostasis and survival of cancer cells upon glutathione depletion. Cell Metab 29, 1166– 1181.e6 (2019). 30799286 PMC6506399
  64. [70]Leu JI, Murphy ME & George DL Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc. Natl Acad. Sci. USA 116, 8390– 8396 (2019). 30962386 PMC6486733
  65. [71]Barayeu U Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals. Nat. Chem. Biol 19, 28– 37 (2022). 36109647 PMC7613997
  66. [72]Wu Z Hydropersulfides inhibit lipid peroxidation and protect cells from ferroptosis. J. Am. Chem. Soc 144, 15825– 15837 (2022). 35977425
  67. [73]Kang YP Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab 33, 174– 189.e7 (2021). 33357455 PMC7839835
  68. [74]Chen L NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat. Metab 1, 404– 415 (2019). 31058257 PMC6489125
  69. [75]Shimada K, Hayano M, Pagano NC & Stockwell BR 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). 26853626 PMC4792701
  70. [76]Yan B Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81, 355– 369.e10 (2021). 33321093
  71. [77]Zou Y Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol 16, 302– 309 (2020). 32080622 PMC7353921
  72. [78]Ding CC MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab 2, 270– 277 (2020). 32462112 PMC7252213
  73. [79]Nguyen KT The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis. Nat. Cell Biol 24, 1239– 1251 (2022). 35941365
  74. [80]Yagoda N RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864– 868 (2007). 17568748 PMC3047570
  75. [81]Gaschler MM Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem. Biol 13, 1013– 1020 (2018). 29512999 PMC5960802
  76. [82]Bogacz M & Krauth-Siegel RL Tryparedoxin peroxidase-deficiency commits trypanosomes to ferroptosis-type cell death. eLife 7, e37503 (2018). 30047863 PMC6117152
  77. [83]Guo Y Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction. Nat. Chem. Biol 19, 468– 477 (2023). 36635564
  78. [84]Ahola S OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab 34, 1875– 1891.e7 (2022). 36113464
  79. [85]Guerra RM & Pagliarini DJ Coenzyme Q biochemistry and biosynthesis. Trends Biochem. Sci 48, 463– 476 (2023). 36702698 PMC10106368
  80. [86]Deshwal S Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat. Cell Biol 25, 246– 257 (2023). 36658222 PMC9928583
  81. [87]Blomme A 2,4-Dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nat. Commun 11, 2508 (2020). 32427840 PMC7237503
  82. [88]Nassar ZD Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. eLife 9, e54166 (2020). 32686647 PMC7386908
  83. [89]Gao M Role of mitochondria in ferroptosis. Mol. Cell 73, 354– 363.e3 (2019). 30581146 PMC6338496
  84. [90]Conlon M A compendium of kinetic modulatory profiles identifies ferroptosis regulators. Nat. Chem. Biol 17, 665– 674 (2021). 33686292 PMC8159879
  85. [91]Zhang T ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat. Cancer 3, 75– 89 (2022). 35121990
  86. [93]Kalkavan H Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356– 3374.e22 (2022). 36055199 PMC9450215
  87. [94]Tarangelo A Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity. Life Sci. Alliance 5, e202101157 (2022). PMC8807879 35074928
  88. [95]Wu S A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. Proc. Natl Acad. Sci. USA 119, e2121987119 (2022). PMC9245637 35749365
  89. [96]Yang C De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat. Cell Biol 25, 836– 847 (2023). 37291265
  90. [97]Wang F PALP: a rapid imaging technique for stratifying ferroptosis sensitivity in normal and tumor tissues in situ. Cell Chem. Biol 29, 157– 170.e6 (2022). 34813762 PMC8792350
  91. [99]Ubellacker JM Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113– 118 (2020). 32814895 PMC7484468
  92. [100]Mann J Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury. Cell Chem. Biol 10.1016/j.chembiol.2023.10.012 (2023). PMC10922137 37944523 · DOI
  93. [101]Perez MA, Magtanong L, Dixon SJ & Watts JL Dietary lipids induce ferroptosis in Caenorhabditis elegans and human cancer cells. Dev. Cell 54, 447– 454.e4 (2020). 32652074 PMC7483868
  94. [102]Lee JY Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc. Natl Acad. Sci. USA 117, 32433– 32442 (2020). 33288688 PMC7768719
  95. [103]Yamane D 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). 34520742 PMC8913804
  96. [104]Xin S MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling. Cell Death Differ 29, 670– 686 (2022). 34663908 PMC8901757
  97. [105]Dixon SJ Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol 10, 1604– 1609 (2015). 25965523 PMC4509420
  98. [106]Doll S ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol 13, 91– 98 (2017). 27842070 PMC5610546
  99. [107]Bartolacci C Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer. Nat. Commun 13, 4327 (2022). 35882862 PMC9325712
  100. [108]Radif Y 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). 29450800 PMC6182735
  101. [109]Kuch EM Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. Biochim. Biophys. Acta 1841, 227– 239 (2014). 24201376
  102. [110]Poppelreuther M 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). 22357706 PMC3329388
  103. [111]Zhu XG CHP1 regulates compartmentalized glycerolipid synthesis by activating GPAT4. Mol. Cell 74, 45– 58.e7 (2019). 30846317 PMC6450717
  104. [112]Beharier O PLA2G6 guards placental trophoblasts against ferroptotic injury. Proc. Natl Acad. Sci. USA 117, 27319– 27328 (2020). 33087576 PMC7959495
  105. [113]Sun WY Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nat. Chem. Biol 17, 465– 476 (2021). 33542532 PMC8152680
  106. [115]Reed A LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from ferroptosis. ACS Chem. Biol 17, 1607– 1618 (2022). 35658397
  107. [116]Liang D Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186, 2748– 2794.e22 (2023). 37267948 PMC10330611
  108. [117]Rodencal J Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest. Cell Chem. Biol 10.1016/j.chembiol.2023.10.011 (2023). PMC10925838 37963466 · DOI
  109. [118]Zhao Y Identification and characterization of a major liver lysophosphatidylcholine acyltransferase. J. Biol. Chem 283, 8258– 8265 (2008). 18195019
  110. [119]Mishra RS, Carnevale KA & Cathcart MK iPLA2β: front and center in human monocyte chemotaxis to MCP-1. J. Exp. Med 205, 347– 359 (2008). 18208975 PMC2271028
  111. [120]Friedmann Angeli JP 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Preprint at Res. Sq 10.21203/rs.3.rs-943221/v1 (2021). · DOI
  112. [121]Yamada N DHCR7 as a novel regulator of ferroptosis in hepatocytes. Preprint at bioRxiv 10.1101/2022.06.15.496212 (2022). · DOI
  113. [122]Garcia-Bermudez J Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118– 122 (2019). 30760928 PMC6405297
  114. [123]Schumacher MM & DeBose-Boyd RA Posttranslational regulation of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol. Annu. Rev. Biochem 90, 659– 679 (2021). 34153214
  115. [124]Conrad M & Proneth B Selenium: tracing another essential element of ferroptotic cell death. Cell Chem. Biol 27, 409– 419 (2020). 32275866
  116. [125]Yi J, Zhu J, Wu J, Thompson CB & Jiang X Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc. Natl Acad. Sci. USA 117, 31189– 31197 (2020). 33229547 PMC7733797
  117. [126]Vangala JR, Sotzny F, Kruger E, Deshaies RJ & Radhakrishnan SK Nrf1 can be processed and activated in a proteasome-independent manner. Curr. Biol 26, R834– R835 (2016). 27676297 PMC6156719
  118. [127]Tomlin FM Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity. ACS Cent. Sci 3, 1143– 1155 (2017). 29202016 PMC5704294
  119. [128]Chavarria C ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation. iScience 26, 107777 (2023). 37720101 PMC10502413
  120. [129]Dirac-Svejstrup AB DDI2 Is a ubiquitin-directed endoprotease responsible for cleavage of transcription factor NRF1. Mol. Cell 79, 332– 341.e7 (2020). 32521225 PMC7369636
  121. [130]Forcina GC Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proc. Natl Acad. Sci. USA 119, e2118646119 (2022). PMC8931371 35271393
  122. [131]Kotschi S NFE2L1-mediated proteasome function protects from ferroptosis. Mol. Metab 57, 101436 (2022). 34999280 PMC8814388
  123. [132]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). 35435658
  124. [133]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). 36776554 PMC9911892
  125. [134]Olzmann JA & Carvalho P Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol 20, 137– 155 (2019). 30523332 PMC6746329
  126. [135]Dierge E 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). 34118189
  127. [136]Minami JK CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis. Cancer Cell 41, 1048– 1060.e9 (2023). 37236196 PMC10330677
  128. [137]Lee H Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance. Nat. Commun 15, 79 (2024). 38167301 PMC10761718
  129. [138]Zou Y A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun 10, 1617 (2019). 30962421 PMC6453886
  130. [139]Ferrada L, Barahona MJ, Vera M, Stockwell BR & Nualart F Dehydroascorbic acid sensitizes cancer cells to system xc− inhibition-induced ferroptosis by promoting lipid droplet peroxidation. Cell Death Dis 14, 637 (2023). 37752118 PMC10522586
  131. [140]Mohammadyani D Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: mass spectrometry and coarse-grained simulations. Free Radic. Biol. Med 76, 53– 60 (2014). 25110833 PMC4276254
  132. [141]Perez MA Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity. PLoS Genet 18, e1010436 (2022). 36178986 PMC9555615
  133. [142]Alborzinia H Golgi stress mediates redox imbalance and ferroptosis in human cells. Commun. Biol 1, 210 (2018). 30511023 PMC6262011
  134. [143]Huang Y 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). 35379328 PMC8981649
  135. [144]Nakagawa K Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468, 117– 121 (2010). 20953171
  136. [145]Rost S Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537– 541 (2004). 14765194
  137. [146]Jin DY A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. Nat. Commun 14, 828 (2023). 36788244 PMC9929328
  138. [147]Yang X Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell Metab 35, 1474– 1490.e8 (2023). 37467745 PMC10529626
  139. [148]Mugoni V Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 152, 504– 518 (2013). 23374346 PMC3574195
  140. [149]Jo Y & DeBose-Boyd RA Post-translational regulation of HMG CoA reductase. Cold Spring Harb. Perspect. Biol 14, a041253 (2022). 35940903 PMC9732902
  141. [152]Gao M Ferroptosis is an autophagic cell death process. Cell Res 26, 1021– 1032 (2016). 27514700 PMC5034113
  142. [153]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). 33245979
  143. [154]Anandhan A NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci. Adv 9, eade9585 (2023). 36724221 PMC9891695
  144. [155]Wu Z Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl Acad. Sci. USA 116, 2996– 3005 (2019). 30718432 PMC6386716
  145. [156]Wu K Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. Nat. Cell Biol 25, 714– 725 (2023). 37156912
  146. [157]Dixon SJ & Stockwell BR The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol 10, 9– 17 (2014). 24346035
  147. [158]Swanda RV Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response. Mol. Cell 10, 3347– 3359.e9 (2023). PMC10529971 37647899
  148. [159]Zhang Y mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun 12, 1589 (2021). 33707434 PMC7952727
  149. [161]Dolma S, Lessnick SL, Hahn WC & Stockwell BR Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285– 296 (2003). 12676586
  150. [162]Vaca CE & Harms-Ringdahl M Nuclear membrane lipid peroxidation products bind to nuclear macromolecules. Arch. Biochem. Biophys 269, 548– 554 (1989). 2493218
  151. [163]Zhang Y Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol 26, 623– 633.e9 (2019). 30799221 PMC6525071
  152. [164]Tarangelo A p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep 22, 569– 575 (2018). 29346757 PMC5791910
  153. [165]Muller F Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ 30, 442– 456 (2023). 36443441 PMC9950476
  154. [166]Koppula P A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun 13, 2206 (2022). 35459868 PMC9033817
  155. [167]Takahashi N 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). 33128871 PMC7718371
  156. [168]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). 33539732
  157. [169]Viswanathan VS Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453– 457 (2017). 28678785 PMC5667900
  158. [170]Wang W CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270– 274 (2019). 31043744 PMC6533917
  159. [171]Wang L ATF3 promotes erastin-induced ferroptosis by suppressing system Xc−. Cell Death Differ 27, 662– 675 (2020). 31273299 PMC7206049
  160. [172]Wu J Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402– 406 (2019). 31341276 PMC6697195
  161. [173]Venkatesh D MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes Dev 34, 526– 543 (2020). 32079652 PMC7111265
  162. [174]Liu J NUPR1 is a critical repressor of ferroptosis. Nat. Commun 12, 647 (2021). 33510144 PMC7843652
  163. [175]Alborzinia H MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat. Cancer 3, 471– 485 (2022). 35484422 PMC9050595
  164. [176]Floros KV MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc−/glutathione axis. Cancer Res 81, 1896– 1908 (2021). 33483374 PMC9281612
  165. [177]Zhang Y, Koppula P & Gan B Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1. Cell Cycle 18, 773– 783 (2019). 30907299 PMC6527290
  166. [178]Valente LJ p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen. J. Cell Biol 219, e201908212 (2020). PMC7594498 32886745
  167. [179]Wohlhieter CA Concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence in lung cancer. Cell Rep 33, 108444 (2020). 33264619 PMC7722473
  168. [180]Zhao Y HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep 33, 108487 (2020). 33296645
  169. [181]Tesfay L Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res 79, 5355– 5366 (2019). 31270077 PMC6801059
  170. [182]Lee H Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol 22, 225– 234 (2020). 32029897 PMC7008777
  171. [183]Acoba MG, Senoo N & Claypool SM Phospholipid ebb and flow makes mitochondria go. J. Cell Biol 219, e202023131 (2020). PMC7401802 32614384
  172. [184]Barger SR, Penfield L & Bahmanyar S Coupling lipid synthesis with nuclear envelope remodeling. Trends Biochem. Sci 47, 52– 65 (2022). 34556392 PMC9943564
  173. [185]Zhang HL PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol 24, 88– 98 (2022). 35027735
  174. [186]Wu Y Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2. Dev. Cell 58, 376– 397.e4 (2023). 36858041
  175. [187]Cui S Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases. Mol. Cell 83, 3931– 3939.e5 (2023). 37863053 PMC10841858
  176. [188]Rodencal J & Dixon SJ Positive feedback amplifies ferroptosis. Nat. Cell Biol 24, 4– 5 (2022). 35027732
  177. [189]Brown CW Prominin2 drives ferroptosis resistance by stimulating iron export. Dev. Cell 51, 575– 586.e4 (2019). 31735663 PMC8316835
  178. [190]Zhao Y Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab 35, 1688– 1703.e10 (2023). 37793345 PMC10558089
  179. [191]Feng H Transferrin receptor is a specific ferroptosis marker. Cell Rep 30, 3411– 3423.e7 (2020). 32160546 PMC7172030
  180. [192]Jia M Redox homeostasis maintained by GPX4 facilitates STING activation. Nat. Immunol 21, 727– 735 (2020). 32541831
  181. [193]Xie Y The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 20, 1692– 1704 (2017). 28813679
  182. [195]Tian R Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat. Neurosci 24, 1020– 1034 (2021). 34031600 PMC8254803
  183. [196]Ryan SK Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nat. Neurosci 26, 12– 26 (2023). 36536241 PMC9829540
  184. [197]Linkermann A Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836– 16841 (2014). 25385600 PMC4250130
  185. [198]Brown CW, Amante JJ & Mercurio AM 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). 29934307 PMC6102132
  186. [199]Dar HH Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium. J. Clin. Invest 128, 4639– 4653 (2018). 30198910 PMC6159971
  187. [200]Belavgeni A vPIF-1 is an insulin-like antiferroptotic viral peptide. Proc. Natl Acad. Sci. USA 120, e2300320120 (2023). PMC10214148 37186845
  188. [201]Jin J Machine learning classifies ferroptosis and apoptosis cell death modalities with TfR1 immunostaining. ACS Chem. Biol 17, 654– 660 (2022). 35230809 PMC8938922
  189. [202]Shimada K Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol 12, 497– 503 (2016). 27159577 PMC4920070
  190. [203]Murphy TH, Miyamoto M, Sastre A, Schnaar RL & Coyle JT Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2, 1547– 1558 (1989). 2576375
  191. [204]Tan S, Schubert D & Maher P Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem 1, 497– 506 (2001). 11895126
  192. [205]Ratan RR, Murphy TH & Baraban JM 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). 8027786 PMC6577015
  193. [206]Wiernicki B Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis. Cell Death Dis 11, 922 (2020). 33110056 PMC7591475
  194. [208]Poon JF, Zilka O & Pratt DA Potent ferroptosis inhibitors can catalyze the cross-dismutation of phospholipid-derived peroxyl radicals and hydroperoxyl radicals. J. Am. Chem. Soc 142, 14331– 14342 (2020). 32698570
  195. [209]Hadian K & Stockwell BR A roadmap to creating ferroptosis-based medicines. Nat. Chem. Biol 17, 1113– 1116 (2021). 34675413 PMC8990224
  196. [211]Hendricks JM Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol 30, 1090– 1103.e7 (2023). 37178691 PMC10524360
  197. [212]Nakamura T Phase separation of FSP1 promotes ferroptosis. Nature 619, 371– 377 (2023). 37380771 PMC10338336
  198. [213]Farmer LA 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). 35921655
  199. [214]Jelinek A Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic. Biol. Med 117, 45– 57 (2018). 29378335
  200. [215]Fang X Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672– 2680 (2019). 30692261 PMC6377499

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Authors
Dixon, S. J., & Olzmann, J. A.
Affiliations
  • Stanford University (US)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
  • Dixon, Scott J.
  • Olzmann, James A.
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2024-02-16
Volume
25
Issue
6
Pages
424-442
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-024-00703-5
PMC
PMC12187608
OpenAlex
W4391878282
Cited by
1,596
References
16
Citations by year
2026: 819 · 2025: 619 · 2024: 158
FWCI
117.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM112948, R01GM122923)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128099)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
ferroptosis, non-apoptotic cell death, lipid peroxidation, iron metabolism, plasma membrane ion transport, mitochondrial metabolism, endoplasmic reticulum, lipid droplets, peroxisomes, redox homeostasis, transcription factors, organelle crosstalk
MeSH terms
Ferroptosis, Animals, Cell Membrane, Humans, Iron, Mitochondria, Oxidation-Reduction, Lipid Peroxidation, Lipid Metabolism

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