2. Academic Validation
  3. Screen of FDA-approved drug library identifies vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6

Screen of FDA-approved drug library identifies vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6

  • J Pharm Anal. 2025 May;15(5):101092. doi: 10.1016/j.jpha.2024.101092.
Yifeng Shi 1 2 3,  Sunlong Li 1 2 3,  Shuhao Zhang 1 2 3,  Caiyu Yu 4,  Jiansen Miao 1 2 3,  Shu Yang 1 2 3,  Yan Chen 1 2 3,  Yuxuan Zhu 1 2 3,  Xiaoxiao Huang 5,  Chencheng Zhou 3,  Hongwei Ouyang 6 7,  Xiaolei Zhang 1 2 3,  Xiangyang Wang 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 2 Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang, 325000, China.
  • 3 The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
  • 4 School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
  • 5 The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
  • 6 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 7 Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Hangzhou, 310058, China.
PMID: 40496065 DOI: 10.1016/j.jpha.2024.101092
Abstract

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting Ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited Ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited Ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome Sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit Ferroptosis through the Axl receptor tyrosine kinase (Axl)/phosphatidylinositol 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) axis. Together, we demonstrate that vitamin K inhibits Ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of Axl/PI3K/Akt axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and Other ferroptosis-related diseases.

Keywords

FDA-approved drug library; Ferroptosis; Gas6/AXL; Osteoarthritis; Vitamin K.

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