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

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.