Abstract：
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-44,5, 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.
摘要：
Ferroptosis,以铁依赖性脂质过氧化物1为标志的细胞死亡的非凋亡形式，在器官损伤中具有关键作用，退行性疾病和耐药癌症的脆弱性2。尽管在理解与铁凋亡相关的分子过程方面取得了实质性进展，确定细胞对铁凋亡的敏感性的其他细胞外在和细胞内在过程仍然未知。在这里，我们表明，完全还原形式的维生素K-一组萘醌，包括甲基萘醌和叶醌3-赋予了强大的抗铁功能，除了通过充当γ-谷氨酰羧化酶的辅因子而与血液凝固相关的常规功能。铁凋亡抑制蛋白1（FSP1），NAD（P）H-泛醌还原酶和继谷胱甘肽过氧化物酶-44,5之后的第二个主要铁凋亡控制被发现有效地将维生素K还原为其对苯二酚，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对抗华法林中毒的解毒作用的原因。因此，FSP1是介导经典维生素Kcycle6中华法林抗性维生素K减少的酶。FSP1依赖性非规范维生素K循环可以保护细胞免受有害的脂质过氧化和铁凋亡。
