VKORC1L1-mediated vitamin K recycling counters ferroptosis to promote endothelial repair.

Vitamin K is classically known for hepatic γ-carboxylation via VKORC1, yet accumulating evidence suggests broader redox-regulatory roles. Here, we characterize the VKORC1 paralogue VKORC1L1 as an anti-oxidative enzyme that couples the vitamin K cycle to ferroptosis defense in the endothelium. In human coronary artery endothelial cells (HCAEC), menaquinone-7 (Vitamin K2, MK-7) increased viability and attenuated RSL3-induced lipid peroxidation, ferroptosis, and NF-κB-dependent inflammatory activation. In vivo, a MK-7 enriched diet accelerated reendothelialization after electric carotid injury in C57BL/6J mice without altering hemostasis. Silencing VKORC1L1, but not the coagulation-linked VKORC1, diminished HCAEC proliferation, raised reactive oxygen species, and triggered NF-κB activation. Importantly, MK-7 failed to rescue these effects in VKORC1L1-deficient cells, supporting a functional requirement for VKORC1L1 in vitamin K-mediated cytoprotection. Transcriptomics of VKORC1L1-deficient cells revealed a lipid peroxide/NF-κB/TNF pathway that amplified oxidative inflammation. This signaling axis was blocked by the lipid-radical scavenger ferrostatin-1 or by inhibiting TNF shedding. Collectively, these data identify VKORC1L1 as a redox-responsive component of the endothelial vitamin K cycle that limits lipid peroxides, suppresses ferroptosis, restrains TNF-driven inflammation, and promotes vascular repair.