Astragaloside IV alleviates macrophage senescence and d-galactose-induced bone loss in mice through STING/NF-κB pathway

•AS-IV impedes macrophage senescence and promotes osteogenic differentiation of BMSCs through the modulation of STING/NF-κB.•AS-IV treatment ameliorated macrophage senescence, abnormal bone microstructure, and bone mass loss in a mouse model of SOP. Senile osteoporosis (SOP) is an age-related metabolic bone disease that currently lacks specific therapeutic interventions. Thus, this study aimed to investigate the effect of Astragaloside IV (AS-IV) on macrophage senescence, bone marrow mesenchymal stem cell (BMSC) osteogenesis, and SOP progression. A senescent macrophage model was established and treated with varying concentrations of AS-IV. Cell activity was measured using the CCK8 assay. The senescence levels of macrophages were evaluated through β-galactosidase staining, PCR, and immunofluorescence. Macrophage mitochondrial function was assessed using ROS and JC-1 staining. Macrophage polarization was evaluated through PCR, Western blot, and immunofluorescence. The inhibitory effects of AS-IV on macrophage senescence were investigated using Western blot analysis. Furthermore, the effects of macrophage conditioned medium (CM) on BMSCs osteogenic were detected using ALP, alizarin red, and PCR. AS-IV inhibited macrophage senescence and M1 polarization, alleviated mitochondrial dysfunction, and promoted M2 polarization. Mechanistically, it suppressed the STING/NF-κB pathway in H2O2-activated macrophages. Conversely, the STING agonist c-di-GMP reversed the effects of AS-IV on macrophage senescence. Additionally, AS-IV-induced macrophage CM promoted BMSC osteogenic differentiation. In vivo, AS-IV treatment ameliorated aberrant bone microstructure and bone mass loss in the SOP mouse model, inhibited macrophage senescence, and promoted M2 polarization. By modulating the STING/NF-κB signaling pathway, AS-IV potentially inhibited macrophage senescence and stimulated osteogenic differentiation of BMSCs, thus exerting an anti-osteoporotic effect. Consequently, AS-IV may serve as an effective therapeutic candidate for the treatment of osteoporosis.