Integrating TWAS, chemical-genomic networks, and experimental models: melatonin as a ferroptosis inhibitor in osteoarthritis therapy

These findings demonstrate that melatonin alleviates OA progression by inhibiting ferroptosis and inflammation, offering a novel therapeutic strategy. This study integrates computational and experimental validation to elucidate melatonin's mechanism in OA, supporting its clinical potential. Key points • Identification of melatonin as a potential therapeutic agent for osteoarthritis (OA) by TWAS, CGSEA, and network pharmacology conjoint analysis. • Molecular docking shows strong binding capacity of melatonin to iron death-related proteins (e.g., GPX4, SLC7A11). • Experimentally confirmed that melatonin significantly reversed IL-1β-induced iron death in chondrocytes by restoring SLC7A11/GPX4 expression, inhibiting P53 activation and reducing ROS accumulation.