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

TLDR

Ferroptosis is an iron‑dependent, non‑apoptotic cell death driven by lipid peroxidation, implicated in organ injury, degenerative disease, and therapy‑resistant cancers, yet the cell‑extrinsic and intrinsic determinants of sensitivity remain largely unknown. The study demonstrates that fully reduced vitamin K naphthoquinones act as potent ferroptosis suppressors, with FSP1 catalyzing their reduction to hydroquinone—a radical‑trapping antioxidant that blocks lipid peroxidation and protects cells against ferroptosis, also explaining vitamin K’s antidotal effect on warfarin poisoning.

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.