Stabilization of β-catenin by 7,8-Dihydroxyflavone protects against osteoblast ferroptosis and bone loss in type 2 diabetic osteoporosis.

Type 2 diabetic osteoporosis (T2DOP) is characterized by a long-term imbalance in bone metabolism, where the diabetic environment heightens the risk of fragile fractures and reduces bone density. Emerging evidence highlights ferroptosis as a key mechanism underlying glucolipotoxicity-induced osteoblast death. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived flavonoid with potent antioxidant and anti-ferroptotic properties, has not been thoroughly investigated in the context of T2DOP. First acknowledged in 1984 as a key type of secondary osteoporosis, T2DOP is distinguished by notable cortical porosity and increased bone fragility. Given its complex pathogenesis, further research is crucial. The progression of T2DOP could be significantly influenced by ferroptosis, a form of cell death that depends on iron. This investigation sought to understand the impact of 7,8-DHF on ferroptosis caused by high glucose and palmitic acid (HGPA) and its significance for T2DOP. Using BODIPY-C11 and FerroOrange staining, Western blotting, mitochondrial assays, immunoblotting, and immunofluorescence, we evaluated 7,8-DHF's protective effects on MC3T3-E1 cells. In vivo, micro-CT, H&E staining, calcein-alizarin red double labeling, and immunohistochemistry were employed in a murine T2DOP model. 7,8-DHF significantly inhibited HGPA-induced ferroptosis, reduced lipid peroxidation, lowered ROS levels, and restored osteogenic capacity. Moreover, bone density and GPX4 expression were elevated, and the Wnt/β-catenin pathway was activated. These effects were weakened by β-catenin knockdown., suggesting that 7,8-DHF mitigates T2DOP by modulating Wnt/β-catenin signaling to suppress ferroptosis.