Sirtuin 3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells by regulating macrophage polarization under high glucose.

Under high glucose conditions, the bone repair process is impaired, in which macrophage polarization plays a critical role. This study aims to investigate the role of the Sirtuin 3/Forkhead box O3a (SIRT3/FoxO3a) pathway in regulating macrophage polarization under hyperglycemic conditions and its impact on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). By establishing an in vitro high-glucose model in RAW264.7 macrophages, we found that high glucose suppressed the SIRT3/FoxO3a pathway, leading to increased reactive oxygen species (ROS) levels, reduced autophagy activity, and promoted polarization of macrophages toward the M1 phenotype. In contrast, SIRT3 overexpression reversed these effects, promoting macrophage polarization toward the M2 phenotype. When BMSCs were co-cultured with conditioned medium from macrophages, the medium derived from SIRT3-overexpressing macrophages significantly enhanced the proliferation, migration, and osteogenic differentiation capacity of BMSCs. The findings suggest that targeting the SIRT3/FoxO3a pathway may represent a promising novel strategy for improving bone healing in diabetic patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-33483-9.