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The underlying metabolic basis remains unclear. This study aimed to identify energy\u2010regulating pathways sustaining MSC osteogenesis during aging. Progressive activation of lipophagy was observed during MSC osteogenic differentiation, coupling lipid\u2010droplet degradation with mitochondrial \u03b2\u2010oxidation and ATP generation. Loss of the lipophagy receptor SPARTIN disrupted this process, leading to lipid accumulation, reduced CPT1A\/CPT2 expression, suppressed oxidative phosphorylation, and impaired osteogenesis in vitro and in vivo. Conditional deletion of Spart in MSCs reproduced an osteoporosis\u2010like phenotype in young mice. Reactivation of lipophagy using bone\u2010tropic AAV9\u2010LAP restored mitochondrial metabolism and bone mass in both Spart\u2010CKO and SOP mice. Pharmacological activation with digoxin produced similar effects but induced cardiotoxicity. A senescent\u2010neutrophil\u2010membrane\u2010coated nanoplatform (SNM@NP\u2010DIG) enabled bone\u2010targeted digoxin delivery, rescuing bone mass while minimizing cardiac injury. Overall, SPARTIN\u2010mediated lipophagy is a critical metabolic regulator of MSC osteogenesis and represents a promising therapeutic target for senile osteoporosis.<\/jats:p>","DOI":"10.1002\/advs.75348","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T07:41:42Z","timestamp":1777275702000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Endogenous Lipophagy: A Novel Strategy to Enhance MSC Osteogenesis and Mineralization for Senile Osteoporosis Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Chaoqiang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Eighth Affiliated Hospital ,Sun Yat\u2010Sen University Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhidong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Eighth Affiliated Hospital 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