Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism.

Here, we identified vitamin K epoxide reductase complex subunit 1 like 1 (VKORC1L1) as a potent ferroptosis repressor. VKORC1L1 protects cells from ferroptosis by generating the reduced form of vitamin K, a potent radical-trapping antioxidant, to counteract phospholipid peroxides independent of the canonical GSH/GPX4 mechanism. Notably, we found that VKORC1L1 is also a direct transcriptional target of p53. Activation of p53 induces downregulation of VKORC1L1 expression, thus sensitizing cells to ferroptosis for tumor suppression. Interestingly, a small molecular inhibitor of VKORC1L1, warfarin, is widely prescribed as an FDA-approved anticoagulant drug. Moreover, warfarin represses tumor growth by promoting ferroptosis in both immunodeficient and immunocompetent mouse models. Thus, by downregulating VKORC1L1, p53 executes the tumor suppression function by activating an important ferroptosis pathway involved in vitamin K metabolism. Our study also reveals that warfarin is a potential repurposing drug in cancer therapy, particularly for tumors with high levels of VKORC1L1 expression. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Xin Yang, Zhe Wang, Fereshteh Zandkarimi, Yanqing Liu, Shoufu Duan, Zhiming Li, Ning Kon, Zhiguo Zhang, Xuejun Jiang, Brent R Stockwell, Wei Gu. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell metabolism. 2023 Aug 08;35(8):1474-1490.e8

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PMID: 37467745

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