Screen of FDA-approved drug library identifies vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6.
10.1016/j.jpha.2024.101092
- Author:
Yifeng SHI
1
;
Sunlong LI
1
;
Shuhao ZHANG
1
;
Caiyu YU
2
;
Jiansen MIAO
1
;
Shu YANG
1
;
Yan CHEN
1
;
Yuxuan ZHU
1
;
Xiaoxiao HUANG
3
;
Chencheng ZHOU
4
;
Hongwei OUYANG
5
;
Xiaolei ZHANG
1
;
Xiangyang WANG
1
Author Information
1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
2. School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
3. The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
4. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325003, China.
5. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Publication Type:Journal Article
- Keywords:
FDA-approved drug library;
Ferroptosis;
Gas6/AXL;
Osteoarthritis;
Vitamin K
- From:
Journal of Pharmaceutical Analysis
2025;15(5):101092-101092
- CountryChina
- Language:English
-
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.
