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The pathological mechanism of SOP, which involves impaired osteogenesis of bone marrow\u2010derived mesenchymal stem cells (MSCs), warrants further investigation to facilitate the development of novel therapeutic agents. In this study, we demonstrated that age\u2010related lamin B1 (LMNB1) deficiency in SOP\u2010MSCs led to lamina\u2010associated domain (LAD) detachment, causing super\u2010enhancer (SE) formation to effectively drive SLC7A11 expression. Elevated SLC7A11 expression activated disulfidptosis in SOP\u2010MSCs, thereby resulting in disulfide bond formation in actin and subsequent cytoskeleton collapse. The disulfide\u2010crosslinked actin\u2010induced 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\u2010MSCs, aggravating age\u2010related bone loss in SOP. Moreover, we identified the FDA\u2010approved drug naldemedine as a potent inhibitor of SLC7A11\u2010dependent disulfidptosis through virtual molecular screening and confirmed its therapeutic potential for SOP. Our findings explore the connection among age\u2010related LMNB1 deficiency, SLC7A11\u2010dependent disulfidptosis and mitochondrial fission disruption in SOP\u2010MSCs 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.<\/jats:p>","DOI":"10.1002\/advs.78203","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:01:51Z","timestamp":1791518511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Age\u2010Related Lamin B1 Deficiency Activates SLC7A11\u2010Dependent Disulfidptosis to Impair Osteogenesis via Intercepting Mitochondrial Fission"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0684-5237","authenticated-orcid":false,"given":"Wenhui","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Eighth Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen P. R. China"},{"name":"Guangdong Provincial Clinical Research Center for Orthopedic Diseases  Shenzhen P. R. 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