Age-Related Lamin B1 Deficiency Activates SLC7A11-Dependent Disulfidptosis to Impair Osteogenesis via Intercepting Mitochondrial Fission.

Senile osteoporosis (SOP) is an aging-related disease characterized by decreased bone mass and susceptibility to fracture. The pathological mechanism of SOP, which involves impaired osteogenesis of bone marrow-derived mesenchymal stem cells (MSCs), warrants further investigation to facilitate the development of novel therapeutic agents. In this study, we demonstrated that age-related lamin B1 (LMNB1) deficiency in SOP-MSCs led to lamina-associated domain (LAD) detachment, causing super-enhancer (SE) formation to effectively drive SLC7A11 expression. Elevated SLC7A11 expression activated disulfidptosis in SOP-MSCs, thereby resulting in disulfide bond formation in actin and subsequent cytoskeleton collapse. The disulfide-crosslinked actin-induced cytoskeleton disorganization further disrupted their binding with DRP1, inducing mitophagy and oxidative phosphorylation dysfunction by intercepting mitochondrial fission. The resulting mitochondrial disorders impaired the osteogenesis of SOP-MSCs, aggravating age-related bone loss in SOP. Moreover, we identified the FDA-approved drug naldemedine as a potent inhibitor of SLC7A11-dependent disulfidptosis through virtual molecular screening and confirmed its therapeutic potential for SOP. Our findings explore the connection among age-related LMNB1 deficiency, SLC7A11-dependent disulfidptosis and mitochondrial fission disruption in SOP-MSCs and reveal their roles in the molecular mechanism of impaired osteogenesis in SOP. These data contribute to a better understanding of SOP pathogenesis and provide insight into potential clinical treatments.