3,4-二甲氧基查尔酮通过STAT3-Nrf2信号通路抑制铁死亡保护激素性股骨头坏死

Abstract

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently encountered complication in orthopedic practice, yet its precise pathogenic mechanisms remain incompletely understood. Dysregulation of bone metabolism induced by glucocorticoids (GCs) is considered a key contributing factor. 3,4-Dimethoxychalcone (3,4DC), an organic compound, has shown potential biological activities, but its role in the context of GIONFH has not been elucidated. This study investigates the protective effects and underlying mechanisms of 3,4DC against dexamethasone (Dex)-induced ferroptosis and its therapeutic potential in GIONFH.A rat model of GIONFH was established through intraperitoneal administration of Dex, and in vitro studies were performed by culturing osteoblasts (OBs) under Dex treatment conditions. To evaluate the effects of 3,4DC on Dex-treated OBs, we employed C11-BODIPY and FerroOrange staining, assessed mitochondrial function, and analyzed protein expression via Western blot and immunofluorescence. The impact of 3,4DC on the bone microarchitecture of the femoral head in rats was further examined using micro-CT, H&E staining, as well as immunofluorescence and immunohistochemistry at both imaging and histological levels. Our results indicate that 3,4DC effectively inhibits Dex-induced ferroptosis and attenuates the development of GIONFH. In vitro, 3,4DC treatment significantly increased glutathione (GSH) levels while reducing malondialdehyde (MDA) production, lipid peroxidation, and mitochondrial reactive oxygen species (ROS) accumulation. Furthermore, 3,4DC enhanced STAT3 phosphorylation, upregulated glutathione peroxidase 4 (GPX4) and osteogenesis-related proteins, and promoted bone formation. Mechanistically, 3,4DC activated the STAT3/Nrf2 signaling pathway.