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
;
Shuhao ZHANG
;
Caiyu YU
;
Jiansen MIAO
;
Shu YANG
;
Yan CHEN
;
Yuxuan ZHU
;
Xiaoxiao HUANG
;
Chencheng ZHOU
;
Hongwei OUYANG
;
Xiaolei ZHANG
;
Xiangyang WANG
Author Information
1. Department of Orthopaedics,The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Wenzhou,Zhejiang,325000,China;Key Laboratory of Orthopaedics of Zhejiang Province,Wenzhou,Zhejiang,325000,China;The Second School of Medicine,Wenzhou Medical University,Wenzhou,Zhejiang,325003,China
- Publication Type:Journal Article
- Keywords:
Osteoarthritis;
Ferroptosis;
FDA-approved drug library;
Vitamin K;
Gas6/AXL
- From:
Journal of Pharmaceutical Analysis
2025;15(5):1033-1047
- 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.
