Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation¹, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers². Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone³—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4^4,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle⁶. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.

铁死亡是一种以铁依赖性脂质过氧化为标志的非细胞凋亡形式的细胞死亡¹，在器官损伤、退行性疾病和治疗耐药性癌症的脆弱性²中起着关键作用。尽管在理解与铁死亡相关的分子过程方面取得了实质性进展，但决定细胞对铁死亡敏感性的其他细胞外在和细胞内在过程仍然未知。在这里，我们展示了维生素 K 的完全还原形式——一组萘醌，包括甲萘醌和叶绿醌³-除了通过作为 γ-谷氨酰羧化酶的辅因子与血液凝固相关的常规功能外，还具有强大的抗铁死亡功能。铁死亡抑制蛋白 1 (FSP1) 是一种 NAD(P)H-泛醌还原酶，是继谷胱甘肽过氧化物酶 4 ^4,5之后控制铁死亡的第二大支柱，被发现可有效地将维生素 K 还原为其氢醌，一种有效的自由基捕获抗氧化剂和（磷酸）脂质过氧化抑制剂。FSP1 介导的维生素 K 减少也是维生素 K 对华法林中毒的解毒作用的原因。由此可见，FSP1 是介导典型维生素 K 循环^{6中抗华法林维生素 K 减少的酶}. FSP1 依赖的非经典维生素 K 循环可以保护细胞免受有害的脂质过氧化和铁死亡。