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.

神秘的脂质过氧化产物被认为是铁死亡的直接执行者——铁死亡是一种由谷胱甘肽过氧化物酶 4 (GPX4) 不足引发的特殊死亡程序。利用定量氧化还原脂质组学、反向遗传学、生物信息学和系统生物学，我们发现铁死亡涉及高度组织化的氧合中心，其中内质网相关区室中的氧化仅发生在一类磷脂（磷脂酰乙醇胺（PE））上，并且对两个脂肪酰基——花生四烯酰基（AA）和肾上腺酰基（AdA）。通过遗传或药理学抑制酰基辅酶 A 合酶 4 (ACSL4) 来抑制 AA 或 AdA 酯化为 PE，作为一种特定的抗铁死亡救援途径。脂氧合酶 (LOX) 产生双氧合和三氧合 (15-氢过氧)-二酰化 PE 物质，充当死亡信号，而生育酚和生育三烯酚（维生素 E）则抑制 LOX 并防止铁死亡，表明维生素 E 具有稳态生理作用。这种氧化性 PE 死亡途径也可能代表药物发现的目标。