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We demonstrated that tibial fracture surgery led to cognitive dysfunction in 18\u2010month\u2010old mice, concomitant with a reduction in hippocampal levels of cholesterol and its key metabolite 24\u2010hydroxycholesterol (24\u2010OHC). Clinically, reduced blood 24\u2010OHC levels were associated with cognitive decline in elderly surgery patients. Mechanistically, downregulation of sterol regulatory element\u2010binding protein 2 (SREBP2) in reactive astrocytes of the hippocampal dorsal CA1 (dCA1) region was an important cause of postoperative cholesterol deficiency, which in turn impaired synaptic plasticity and excitatory synaptic transmission; furthermore, this deficit could be rescued by direct cholesterol replenishment in the dCA1. Importantly, we established multiple effective therapeutic strategies\u2014astrocyte\u2010specific SREBP2 overexpression, chemogenetic suppression of reactive astrocytes, and minocycline administration\u2014all of which effectively reversed surgery\u2010induced cholesterol loss, alleviated synaptic dysfunction, and ultimately improved cognitive performance. Taken together, our findings not only position astrocytic SREBP2 as a promising therapeutic target for POCD but also highlight the potential diagnostic value of monitoring brain cholesterol metabolism, though this requires validation in larger longitudinal cohorts.<\/jats:p>","DOI":"10.1002\/advs.202519874","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:54:44Z","timestamp":1770886484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neuronal Cholesterol Deficiency Mediated by Astrocytic SREBP2 Downregulation Leads to Postoperative Cognitive Dysfunction Through Impairment of Hippocampal Synaptic Plasticity and Excitatory Synaptic Transmission"],"prefix":"10.1002","volume":"13","author":[{"given":"He","family":"Huang","sequence":"first","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology NMPA Key Laboratory For Research and Evaluation of Narcotic and 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