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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. Screen of FDA-approved drug library identifies Vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2024.101092
Citation: 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. Screen of FDA-approved drug library identifies Vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2024.101092

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

doi: 10.1016/j.jpha.2024.101092
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This work was supported by grants from the Wenzhou Science and Technology Bureau Foundation (ZY2019014)

"Pioneer" and "Leading Goose" R&D Program of Zhejiang (2022C03144) and National Natural Science Foundation of China (82172494, 82372461).

  • Available Online: Aug. 30, 2024
  • 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.
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