Mifepristone ameliorates osteoporosis & hyperlipidemia comorbidity through SPNS3-S1P-S1PR1 axis via regulating BMSCs differentiation.

Osteoporosis (OP) and hyperlipidemia (HLP) are major public health concerns that often coexist in postmenopausal women due to ovarian senescence and metabolic dysregulation. This comorbidity drives bone marrow adipocyte accumulation and impaired osteoblast differentiation, linked to altered mesenchymal stem cell (BMSC) fate, thereby worsening both bone loss and lipid metabolic imbalance. However, the underlying mechanisms remain unclear. The purpose of this study was to identify key regulatory pathways underlying OP-HLP comorbidity and to explore potential therapeutic strategies targeting dysregulated BMSC differentiation. To investigate, we developed a murine OP-HLP comorbidity model by combining ovariectomy with a high-fat diet. BMSCs were induced under osteogenic or adipogenic conditions to assess differentiation patterns, while omics-based bioinformatics identified targets and pathways relevant to OP-HLP. Potential therapeutic agents were then screened virtually and validated experimentally. The results identified the SPNS lysolipid transporter 3 (SPNS3)-sphingosine-1-phosphate (S1P)-S1PR1 axis as a critical regulator of BMSCs differentiation. Mifepristone (MIF), acting as a structural stabilizer of SPNS3, enhanced osteogenic differentiation while inhibiting adipogenesis in vitro. In vivo, MIF significantly improved bone formation and reduced marrow adiposity in OP-HLP mice. In conclusion, this study highlighted the SPNS3-S1P-S1PR1 axis as a novel therapeutic target and suggested repurposing MIF for treating OP-HLP comorbidity. This study provides mechanistic insight into bone-lipid crosstalk and opens opportunities for improved intervention strategies.