In addition, all three vitamin K forms prevented glutamate-induced neuronal ferroptosis, whereas they failed to protect against other types of cell death, except protection of pyroptosis by menadione 18 (Extended Data Fig.
(Fig.1d 1d and Supplementary Videos 1 and 2), as well as in other cancer and non-cancer cell lines (Extended Data Fig.
Phylloquinone, MK4 and menadione also efficiently rescued cells from ferroptosis triggered by well-established ferroptosis inducers 17 including a GPX4 inhibitor ( 1S,3R)-RS元 (RS元) in fibrosarcoma HT-1080 cells (Fig. The anti-ferroptotic activity of vitamin K was not only limited to mouse fibroblasts, as it also prevented ferroptosis in the human cancer cell lines A375 and 786-O that lack GPX4 expression (Fig. Phylloquinone is obtained mostly from leafy green vegetables, and can be converted to MK4 in the body, whereas menadione is a synthetic variant. Notably, besides α-tocopherol (α-TOH), the most biologically active form of vitamin E, only the three forms of vitamin K, phylloquinone, menaquinone-4 (MK4) and menadione, rescued cells from ferroptosis induced by Gpx4 deletion (Fig. To interrogate whether there are other systems besides the aforementioned intrinsic and extrinsic mechanisms that efficiently prevent ferroptosis, we systematically studied a number of naturally available vitamin compounds in mouse embryonic fibroblasts with tamoxifen (TAM)-inducible deletion of Gpx4 (referred to as Pfa1 cells 8) (Extended Data Fig. Vitamin K is a potent anti-ferroptotic compound The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle 6. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning.
Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4 4, 5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone 3-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. 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. Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation 1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers 2.
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