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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\u2014a group of naphthoquinones that includes menaquinone and phylloquinone\n                    <jats:sup>3<\/jats:sup>\n                    \u2014confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for \u03b3-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4\n                    <jats:sup>4,5<\/jats:sup>\n                    , 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 cycle\n                    <jats:sup>6<\/jats:sup>\n                    . The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.\n                  <\/jats:p>","DOI":"10.1038\/s41586-022-05022-3","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T12:02:34Z","timestamp":1659528154000},"page":"778-783","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":748,"title":["A non-canonical vitamin K cycle is a potent ferroptosis 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