{Reference Type}: Journal Article
{Title}: A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
{Author}: Mishima E;Ito J;Wu Z;Nakamura T;Wahida A;Doll S;Tonnus W;Nepachalovich P;Eggenhofer E;Aldrovandi M;Henkelmann B;Yamada KI;Wanninger J;Zilka O;Sato E;Feederle R;Hass D;Maida A;Mourão ASD;Linkermann A;Geissler EK;Nakagawa K;Abe T;Fedorova M;Proneth B;Pratt DA;Conrad M;Mishima E;Ito J;Wu Z;Nakamura T;Wahida A;Doll S;Tonnus W;Nepachalovich P;Eggenhofer E;Aldrovandi M;Henkelmann B;Yamada KI;Wanninger J;Zilka O;Sato E;Feederle R;Hass D;Maida A;Mourão ASD;Linkermann A;Geissler EK;Nakagawa K;Abe T;Fedorova M;Proneth B;Pratt DA;Conrad M;Mishima E;Ito J;Wu Z;Nakamura T;Wahida A;Doll S;Tonnus W;Nepachalovich P;Eggenhofer E;Aldrovandi M;Henkelmann B;Yamada KI;Wanninger J;Zilka O;Sato E;Feederle R;Hass D;Maida A;Mourão ASD;Linkermann A;Geissler EK;Nakagawa K;Abe T;Fedorova M;Proneth B;Pratt DA;Conrad M;
{Journal}: Nature
{Volume}: 608
{Issue}: 7924
{Year}: 08 2022
{Factor}: 69.504
{DOI}: 10.1038/s41586-022-05022-3
{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.