Screen of FDA-approved drug library identifies vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6
Yifeng Shi, Sunlong Li, Shuhao Zhang, Caiyu Yu, Jiansen Miao, Shu Yang, Yan Chen, Yuxuan Zhu, Xiaoxiao Huang, Chencheng Zhou, Hongwei Ouyang, Xiaolei Zhang, Xiangyang Wang
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/PI3K/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. • A group of FDA-approved anti-ferroptotic drugs was identified • Vitamin K inhibits ferroptosis and reduces extracellular matrix degradation • Anti-ferroptotic effects of vitamin K were mediated through Gas6 • Exogenous expression of Gas6 inhibits ferroptosis via the AXL/PI3K/AKT pathway