Abstract

Osteoporosis, a prevalent metabolic bone disorder, is characterized by an imbalance in bone marrow mesenchymal stem cells (BMSCs) differentiation, leading to bone loss, ectopic adipogenesis, and chronic inflammation. Isoliquiritigenin (ISL), a natural compound derived from Glycyrrhiza uralensis, possesses anti-inflammatory and immunomodulatory properties and has been reported to inhibit osteoclast activity. However, its effects and underlying mechanisms regarding BMSCs differentiation remain unclear. In this study, we demonstrated that ISL promotes osteogenic differentiation and suppresses adipogenic differentiation of BMSCs. Furthermore, ISL restored osteogenic capacity under inflammatory conditions. RNA sequencing revealed that ISL activates an integrated ERK1/2-mTOR-HIF-1α signaling axis and enhances downstream glycolysis, a process essential for augmenting the osteogenic potential of BMSCs. Mechanistically, ISL-induced ERK1/2 activation promoted mTOR signaling, thereby increasing HIF-1α expression at both transcriptional and translational levels. Subsequent upregulation of glycolysis provided the necessary energy for osteogenic differentiation. Concurrently, ISL remodeled the inflammatory bone marrow microenvironment by mitigating oxidative stress, downregulating pro-inflammatory cytokines, and reprogramming macrophages from the pro-inflammatory M1 toward the anti-inflammatory M2 phenotype. This microenvironmental shift contributed to the recovery of osteogenic differentiation in BMSCs co-cultured with M1 macrophages. In a rat ovariectomy model, ISL treatment effectively attenuated bone loss, reduced marrow adiposity, and decreased local inflammation. Our findings identify ISL as a promising therapeutic candidate for osteoporosis, which acts by concurrently promoting osteogenesis, suppressing adipogenesis, and modulating inflammatory responses to restore bone homeostasis.