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

Area of Science:

• Biomedical Science
• Cell Biology
• Pharmacology

Background:

• Osteoarthritis (OA) is a degenerative joint disease characterized by chondrocyte ferroptosis.
• Current treatments for OA lack effective ferroptosis-targeting drugs.
• Identifying safe and effective anti-ferroptotic agents is crucial for OA therapy.

Purpose of the Study:

• To screen for FDA-approved drugs with anti-ferroptotic properties in chondrocytes.
• To investigate the therapeutic potential of identified drugs in OA models.
• To elucidate the underlying molecular mechanisms of the most effective drug.

Main Methods:

• High-throughput screening of an FDA-approved drug library in chondrocytes.
• Assessment of ferroptosis inhibition and extracellular matrix (ECM) degradation.
• Evaluation of therapeutic efficacy in a destabilization of the medial meniscus (DMM) mouse model.
• Transcriptome sequencing and gene knockdown experiments to identify molecular targets.

Main Results:

• Vitamin K was identified as a potent anti-ferroptotic drug among FDA-approved agents.
• Vitamin K inhibited chondrocyte ferroptosis and alleviated ECM degradation.
• Intra-articular vitamin K injection ameliorated OA phenotype in a DMM mouse model.
• Vitamin K's anti-ferroptotic effect was dependent on growth arrest-specific 6 (Gas6).
• Gas6 inhibited ferroptosis via the AXL/PI3K/AKT signaling pathway.

Conclusions:

• Vitamin K effectively inhibits ferroptosis and alleviates OA progression.
• The therapeutic mechanism involves enhancing Gas6 expression and activating the AXL/PI3K/AKT axis.
• Vitamin K and Gas6 represent potential therapeutic targets for OA and other ferroptosis-related diseases.