A non-canonical vitamin K cycle is a potent ferroptosis suppressor

Nature. 2022 Aug;608(7924):778-783. doi: 10.1038/s41586-022-05022-3. Epub 2022 Aug 3.


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.

MeSH terms

  • Antidotes / pharmacology
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Carbon-Carbon Ligases / metabolism
  • Coenzymes / metabolism
  • Ferroptosis* / drug effects
  • Hydroquinones / metabolism
  • Hydroquinones / pharmacology
  • Lipid Peroxidation / drug effects
  • Oxidation-Reduction
  • S100 Calcium-Binding Protein A4 / metabolism
  • Vitamin K* / metabolism
  • Vitamin K* / pharmacology
  • Warfarin / adverse effects


  • Antidotes
  • Antioxidants
  • Coenzymes
  • Hydroquinones
  • S100 Calcium-Binding Protein A4
  • Vitamin K
  • Warfarin
  • Carbon-Carbon Ligases
  • glutamyl carboxylase
  • hydroquinone