TSPO Governs Bone-Lipid Homeostasis by Redirecting BMSC Differentiation via the PI3K/AKT/β-Catenin Pathway

• TSPO is significantly upregulated in BMSCs from osteoporosis patients and mouse models, correlating with disease severity. • TSPO overexpression suppresses BMSC proliferation, migration, and osteogenesis while promoting senescence and adipogenesis, whereas knockdown enhances osteogenic capacity. • Mechanistically, TSPO inhibits the PI3K/AKT/GSK-3β/β-catenin signaling pathway, thereby impairing osteogenic differentiation. • Targeted silencing of TSPO via AAV-9 in ovariectomized mice improves bone microarchitecture and reduces marrow adiposity, suggesting a novel anabolic therapeutic strategy for osteoporosis.