The study investigates the role of oxidized phosphatidylethanolamines (PE) in ferroptosis, a specialized form of cell death triggered by insufficient glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics, and systems biology, the authors discovered that ferroptosis involves a highly organized oxygenation center where only a specific class of phospholipids, PE, undergoes oxidation in endoplasmic reticulum (ER)-associated compartments, targeting arachidonoyl (AA) and adrenoyl (AdA) fatty acids. Suppression of AA or AdA esterification into PE, either genetically or pharmacologically, acts as a specific anti-ferroptotic rescue pathway. Lipoxygenases (LOX) generate doubly- and triply-oxygenated (15-hydroperoxy)-di-acylated PE species, which act as death signals. Tocopherols and tocotrienols suppress LOX and protect against ferroptosis, suggesting an unexpected homeostatic role for vitamin E. This oxidative PE death pathway may represent a target for drug discovery. The study also highlights the importance of ACSL4, LPCAT3, and LOX in the production of PE-OOH and the potential conservation of LOX-driven selective oxidation of esterified PE as an ancient mechanism of cell death.The study investigates the role of oxidized phosphatidylethanolamines (PE) in ferroptosis, a specialized form of cell death triggered by insufficient glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics, and systems biology, the authors discovered that ferroptosis involves a highly organized oxygenation center where only a specific class of phospholipids, PE, undergoes oxidation in endoplasmic reticulum (ER)-associated compartments, targeting arachidonoyl (AA) and adrenoyl (AdA) fatty acids. Suppression of AA or AdA esterification into PE, either genetically or pharmacologically, acts as a specific anti-ferroptotic rescue pathway. Lipoxygenases (LOX) generate doubly- and triply-oxygenated (15-hydroperoxy)-di-acylated PE species, which act as death signals. Tocopherols and tocotrienols suppress LOX and protect against ferroptosis, suggesting an unexpected homeostatic role for vitamin E. This oxidative PE death pathway may represent a target for drug discovery. The study also highlights the importance of ACSL4, LPCAT3, and LOX in the production of PE-OOH and the potential conservation of LOX-driven selective oxidation of esterified PE as an ancient mechanism of cell death.