Resveratrol offers therapeutic potential in obesity-related osteoarthritis by targeting ferroptosis via G3BP1-SGs/mTOR modulation.

The increased ferroptosis by obesity contributes to the progression of osteoarthritis (OA). Resveratrol has protective effects against obesity-related OA. However, the underlying mechanisms remain unclear. Here, we investigated the mechanism of resveratrol against obesity-related OA using male C57BL/6 mice and chondrocyte models. The results demonstrated that high-fat diet (HFD) and IL-1β exacerbated cartilage damage in mice and chondrocytes, accompanied by worsening indicators of ferroptosis and upregulation of Ras-GTPase-activating protein binding protein 1 (G3BP1) expression and stress granules (SGs) assembly, which responds to environmental stressors such as obesity. Resveratrol alleviated these effects. After G3BP1 was silenced, resveratrol no longer had the effect of inhibiting ferroptosis and reducing cartilage degradation; while mTOR inhibition rescued ferroptosis-related protective proteins. This study suggests that resveratrol exerts protective effects against obesity-related OA, at least in part, by modulating ferroptosis-related changes in chondrocytes through the G3BP1-SGs/mTOR pathway. These findings provide new insights into OA pathogenesis and highlight resveratrol as a promising therapeutic strategy for obesity-related OA.