%0 Journal Article
%T A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
%A Mishima E
%A Ito J
%A Wu Z
%A Nakamura T
%A Wahida A
%A Doll S
%A Tonnus W
%A Nepachalovich P
%A Eggenhofer E
%A Aldrovandi M
%A Henkelmann B
%A Yamada KI
%A Wanninger J
%A Zilka O
%A Sato E
%A Feederle R
%A Hass D
%A Maida A
%A Mourão ASD
%A Linkermann A
%A Geissler EK
%A Nakagawa K
%A Abe T
%A Fedorova M
%A Proneth B
%A Pratt DA
%A Conrad M
%A Mishima E
%A Ito J
%A Wu Z
%A Nakamura T
%A Wahida A
%A Doll S
%A Tonnus W
%A Nepachalovich P
%A Eggenhofer E
%A Aldrovandi M
%A Henkelmann B
%A Yamada KI
%A Wanninger J
%A Zilka O
%A Sato E
%A Feederle R
%A Hass D
%A Maida A
%A Mourão ASD
%A Linkermann A
%A Geissler EK
%A Nakagawa K
%A Abe T
%A Fedorova M
%A Proneth B
%A Pratt DA
%A Conrad M
%A Mishima E
%A Ito J
%A Wu Z
%A Nakamura T
%A Wahida A
%A Doll S
%A Tonnus W
%A Nepachalovich P
%A Eggenhofer E
%A Aldrovandi M
%A Henkelmann B
%A Yamada KI
%A Wanninger J
%A Zilka O
%A Sato E
%A Feederle R
%A Hass D
%A Maida A
%A Mourão ASD
%A Linkermann A
%A Geissler EK
%A Nakagawa K
%A Abe T
%A Fedorova M
%A Proneth B
%A Pratt DA
%A Conrad M
%J Nature
%V 608
%N 7924
%D 08 2022
%M 35922516
%F 69.504
%R 10.1038/s41586-022-05022-3
%X 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.