Oxyberberine Ameliorates Type 2 Diabetic Osteoporosis Through Sirtuin 3‐Associated Regulation of Autophagy and Ferroptosis in Bone Marrow Mesenchymal Stem Cells

ABSTRACT Type 2 diabetic osteoporosis (T2DOP) is characterized by impaired bone formation and dysfunction of bone marrow mesenchymal stem cells (BMSCs) under persistent metabolic stress. This study investigated the osteoprotective effects of Oxyberberine (OBB) and the involvement of sirtuin 3 (Sirt3)‐associated autophagy and ferroptosis. A high‐fat diet/streptozotocin‐induced T2DOP mouse model and high‐glucose‐treated BMSCs were used. Integrated omics, UHPLC‐HRMS, molecular docking, molecular dynamics simulation, and cellular thermal shift assays were used for compound and target evaluation. Osteogenesis, autophagy, oxidative stress, and ferroptosis were assessed using histological, biochemical, fluorescence, and molecular assays. Sirt3 was suppressed using shRNA in BMSCs and systemic adeno‐associated virus‐mediated knockdown in mice. Ferrostatin‐1 was used as a ferroptosis inhibitor. OBB improved trabecular bone microarchitecture and osteogenic indices in T2DOP mice. In high‐glucose‐treated BMSCs, OBB enhanced osteogenic differentiation and autophagy‐associated activity while reducing reactive oxygen species, Fe 2+ accumulation, lipid peroxidation, and mitochondrial abnormalities. OBB also decreased Ac‐SOD2/SOD2 and Ac‐FoxO3a/FoxO3a ratios. Autophagy inhibition weakened the anti‐ferroptotic effects of OBB, whereas Ferrostatin‐1 partially reproduced its anti‐ferroptotic and pro‐osteogenic effects. Sirt3 knockdown attenuated OBB‐associated protective effects in vitro and reduced skeletal protection in vivo. OBB ameliorates diabetic bone deterioration and high‐glucose‐induced BMSC dysfunction, with Sirt3‐associated regulation of autophagy, redox homeostasis, and ferroptosis contributing to its effects. These findings support further evaluation of OBB as a potential pharmacological candidate for T2DOP.