ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1554987
Revealing the mechanisms of warfarin-induced vascular calcification through metabolomics and network toxicology
Provisionally accepted
Zhijiao Zhang1,2
Pengyan Jia1,2
Chunqi Feng1,2
Juan Xu1
Jingmin Zhang1
Niuniu Bai1
Weihong Chen1,2*
Weiqi Gao1,2,3*- 1Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- 2School of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi Province, China
- 3Shanxi Academy of Advanced Research and Innovation (SAARI), Taiyuan, Shanxi Province, China
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Warfarin is widely used in clinical anticoagulation therapy, but the exact mechanism by which it induces vascular calcification (VC) remains unclear. This study aimed to explore the mechanisms of warfarin-induced VC using metabolomics and network toxicology approaches. Initially, normal rats were orally administered warfarin for two weeks, and VC was then assessed by serum biochemistry and histopathology. Subsequently, non-targeted metabolomics was performed to analyze serum metabolite changes. Finally, network toxicology analysis was conducted to identify key targets and signaling pathways associated with warfarin-induced VC, which were further validated using molecular docking, qRT-PCR, and western blot analyses. The results indicated that warfarin induced aortic calcification in rats, and metabolomics identified 32 differential metabolites, mainly involved in pathways such as primary bile acid biosynthesis, steroid hormone biosynthesis, and amino acid metabolism. Network toxicology analysis, molecular docking, and experimental validation showed that warfarin may induce VC by modulating the targets AKT1, TP53, and HSP90AA1, thereby influencing the PI3K-AKT signaling pathway. This study reveals the potential molecular mechanisms underlying warfarin-induced VC, laying a foundation for further mechanistic investigations and providing important insights for the rational clinical application of warfarin.
Keywords: Warfarin, Vascular Calcification, Metabolomics, Network toxicology, Molecular mechanisms
Received: 03 Jan 2025; Accepted: 14 May 2025.
Copyright: © 2025 Zhang, Jia, Feng, Xu, Zhang, Bai, Chen and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Weihong Chen, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
Weiqi Gao, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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