Metformin rescues osteoblast fate in Glucocorticoid-associated osteonecrosis of the femoral head via PERK/CHAC1/GSH-mediated reprogramming of glutathione homeostasis.

Glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) is a refractory, highly disabling bone disease fundamentally driven by oxidative stress-induced osteoblast damage. While metformin has demonstrated substantial potential in regulating bone metabolism, its precise efficacy and underlying molecular mechanisms in the treatment of GA-ONFH remain to be fully elucidated. The present study comprehensively evaluated the protective efficacy of metformin in antagonizing glucocorticoid-induced cytotoxicity. Combining transcriptomic analyses with multidimensional in vitro assays, we identified the specific glutathione (GSH)-degrading enzyme, CHAC1, as a central downstream target mediating osteoblast injury. Mechanistically, metformin exerts its protective effects by targeting and suppressing the PERK/eIF2α/ATF4 endoplasmic reticulum (ER) stress signaling axis, which significantly downregulates the pathological overexpression of CHAC1. This intervention successfully restores intracellular GSH homeostasis, thereby synergistically blocking both mitochondria-dependent apoptosis and lipid peroxidation-driven ferroptosis cascades. Crucially, in a rat model of GA-ONFH, targeted Chac1 knockdown, exogenous GSH supplementation, or pharmacological blockade of the PERK pathway all successfully rescued osteogenic function and significantly delayed the pathological progression of femoral head necrosis. In conclusion, this study not only highlights the critical role of CHAC1-mediated GSH depletion in determining osteoblast fate, but also provides a robust theoretical foundation for repurposing metformin as an early clinical intervention for GA-ONFH via ER stress suppression and redox homeostasis remodeling.