{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVKORC1 and its paralog VKORC1L1 are key enzymes in the vitamin K cycle, which is essential for the post-translational γ‐carboxylation of vitamin K–dependent proteins. VKORC1, best known as the target of coumarin anticoagulants like warfarin, plays a pivotal role in blood coagulation by recycling vitamin K epoxide to vitamin K hydroquinone, thereby facilitating the activation of clotting factors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In contrast, VKORC1L1, although capable of supporting γ‐carboxylation during early development, is most prominently involved in antioxidative functions, reducing vitamin K to its active form to counteract intracellular reactive oxygen species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these canonical roles, emerging data reveal that VKORC1L1 acts as a potent ferroptosis repressor by generating reduced vitamin K which traps radicals, thereby mitigating phospholipid peroxidation. This enzyme is also a downstream target of p53; p53‐mediated downregulation of VKORC1L1 sensitizes cells to ferroptosis, highlighting a novel tumor suppression mechanism, with therapeutic implications of warfarin as a repurposed anticancer agent."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in vivo studies demonstrate that while VKORC1L1 can partially support vitamin K–dependent carboxylation during the perinatal period, its expression remains relatively constant, with full hemostatic function in adults relying primarily on VKORC1. Interestingly, recent genetic studies indicate that mutations in Vkorc1l1 may also be linked to adipose development and obesity, suggesting broader metabolic roles for this enzyme."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Simone Rost, Andreas Fregin, Vytautas Ivaskevicius, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature02214"}], "href": "https://doi.org/10.1038/nature02214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14765194"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14765194"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michael Caspers, Katrin J Czogalla, Kerstin Liphardt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse: VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.thromres.2015.01.025"}], "href": "https://doi.org/10.1016/j.thromres.2015.01.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25747820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25747820"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Abdessalem Hammed, Benjamin Matagrin, Gabriele Spohn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.457119"}], "href": "https://doi.org/10.1074/jbc.M113.457119"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23928358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23928358"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xin Yang, Zhe Wang, Fereshteh Zandkarimi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2023.06.014"}], "href": "https://doi.org/10.1016/j.cmet.2023.06.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37467745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37467745"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Julie Lacombe, Mark A Rishavy, Kathleen L Berkner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VKOR paralog VKORC1L1 supports vitamin K-dependent protein carboxylation in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.96501"}], "href": "https://doi.org/10.1172/jci.insight.96501"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29321368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29321368"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yi Ding, Jing Cui, Qi Wang, et al. 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