VKORC1L1, short for vitamin K epoxide reductase complex subunit 1 like 1, is a paralog of VKORC1. It functions as a vitamin K oxidoreductase, converting vitamin K epoxide into reduced vitamin K, which is crucial for the γ -carboxylation of several proteins, including coagulation factors and those involved in tissue mineralization [2,3,4]. It also participates in important biological processes such as redox homeostasis and is involved in the vitamin K cycle [2,3]. Genetic models, like knockout mouse models, have been instrumental in studying its function.

In gene knockout studies, Vkorc1 -/-;Vkorc1l1 -/- mice died at birth with severe hemorrhaging, indicating that VKORC1L1 supports carboxylation during the pre-and perinatal periods [4]. Additionally, VKORC1L1 overexpression in liver rescued carboxylation and hemostasis in adult Vkorc1 -/- mice [4]. Moreover, VKORC1L1 was identified as a ferroptosis repressor. Activation of p53, a tumor-suppressor protein, induces down-regulation of VKORC1L1 expression, sensitizing cells to ferroptosis for tumor suppression [1]. Warfarin, an FDA-approved anticoagulant drug and a small molecular inhibitor of VKORC1L1, represses tumor growth by promoting ferroptosis in mouse models [1].

In conclusion, VKORC1L1 is essential for vitamin K-dependent protein carboxylation, especially during pre-and perinatal periods. Its role in tumor suppression through the regulation of ferroptosis via p53-mediated down-regulation has been revealed by model-based research. These findings suggest potential applications in cancer therapy, especially for tumors with high VKORC1L1 expression [1,4].