Metformin exhibits inhibitory effects on ferroptosis and alleviates chondrocyte metabolic imbalance in osteoarthritis models, as well as Erastin-induced ferroptosis, through the modulation of the P53/SLC7A11 pathway.

Osteoarthritis (OA) is a prevalent degenerative disease, and metformin, the first-line treatment for type 2 diabetes, has shown potential in slowing the progression of OA, although its mechanism of action is not fully understood. This study aims to explore the role of ferroptosis in OA and evaluate the therapeutic effects and mechanisms of metformin on ferroptosis. We identified gene differences associated with OA through RNA-Seq data analysis and predicted potential targets using network pharmacology and molecular docking techniques. In vivo experimental methods, including histological examination, immunofluorescence, Western blotting, real-time quantitative PCR, biochemical analysis, and ELISA, were used to study the effects of metformin in the modified Hulth method and Erastin-induced OA models. The study found that metformin significantly inhibits chondrocyte ferroptosis by upregulating SLC7A11 and downregulating P53 expression, maintaining the balance of synthesis and catabolism in chondrocytes, and effectively slowing down the degeneration of knee joint cartilage in rats. Overall, this study not only provides further evidence for the anti-OA effects of metformin but also identifies its direct targets in the inhibition of ferroptosis in OA.