Background <p>Tuberculosis (TB) is a major infectious disease that can lead to systemic complications, including osteoporosis, particularly in immunocompromised individuals. Exosomal miRNAs derived from TB-infected macrophages have been implicated in various pathophysiological processes, including bone metabolism. This study investigates how exosomal miR-125b-5p from TB-infected macrophages contributes to osteoporosis by targeting insulin-like growth factor 2 (IGF2) and modulating the PI3K/AKT signaling pathway.</p> Methods <p>We analyzed NHANES data to compare bone mineral density in TB patients and healthy controls. In vitro experiments were conducted with Mycobacterium tuberculosis-infected peritoneal macrophages from C57BL/6 mice, isolating exosomes and using Western blot, flow cytometry, and bioinformatics tools to assess the role of miR-125b-5p in regulating osteogenic markers. In vivo studies in mouse models were performed to evaluate the impact of exosomal miR-125b-5p on bone density and structure.</p> Results <p>Exosomes from TB-infected macrophages were found to contain elevated levels of miR-125b-5p, which targeted IGF2 and inhibited the PI3K/AKT pathway, leading to impaired osteoblast function and reduced bone formation. Knockdown of miR-125b-5p partially restored osteogenic markers and bone density. Furthermore, IGF2 silencing exacerbated bone loss, confirming the critical role of IGF2 in TB-induced osteoporosis.</p> Conclusion <p>This study demonstrates that miR-125b-5p from TB-infected macrophages promotes osteoporosis by disrupting the IGF2/PI3K/AKT signaling axis. Targeting this pathway could provide a potential therapeutic strategy for managing TB-induced osteoporosis. Further clinical studies are necessary to validate these findings and explore additional therapeutic options.</p> Graphical abstract <p></p>