Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis—a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls—arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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We thank J. Ruzicka (Thermo Fisher Scientific) for help in obtaining MS3 spectra of PE oxidation products using tribrid Fusion Lumos. Supported by the US National Institutes of Health (P01HL114453 to R.K.M., U19AI068021 to J.G., NS076511 to V.E.K., NS061817 to H.B., P41GM103712 to I.B. and ES020693 to Y.Y.T.), the Human Frontier Science Program (HFSP-RGP0013/2014), and the Deutsche Forschungsgemeinschaft (CO 291/2-3 and CO 291/5-1) to M.C.
The authors declare no competing financial interests.
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Kagan, V., Mao, G., Qu, F. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13, 81–90 (2017). https://doi.org/10.1038/nchembio.2238
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