Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

Valerian E Kagan, Gaowei Mao, Feng Qu, Jose Pedro Friedmann Angeli, Sebastian Doll, Claudette St Croix, Haider Hussain Dar, Bing Liu, Vladimir A Tyurin, Vladimir B Ritov, Alexandr A Kapralov, Andrew A Amoscato, Jianfei Jiang, Tamil Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein-Seetharaman, Simon Watkins, Ivet Bahar, Joel Greenberger, Rama K Mallampalli, Brent R Stockwell, Yulia Y Tyurina, Marcus Conrad, Hülya Bayır

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.