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Here, proteomic and transcriptomic analyses in multiple organs from humans and POCD mice are conducted to identify potential peripheral targets for anesthesia\/surgery\u2010induced cognitive impairment. The results show that anesthesia\/surgery can disrupt the blood\u2010brain barrier (BBB) and promote the release of hepatogenous C3 protein into the blood. This surgical dual factors ultimately drove C3 to cross the damaged BBB and selectively colocalize with C3aR in the hippocampus. Anesthesia\/surgery\u2010induced C3 upregulation in the liver is associated with hypomethylation of C3 promoter. Inhibiting hepatogenous C3 is demonstrated to salvage the anesthesia\/surgery\u2010induced cognitive impairment, structural and functional injury of synapse, and C3aR\u2010mediated microglial phagocytosis. Perioperative alterations in serum C3 protein in surgical patients are related to POCD, showing potential for predicting this disorder. This study emphasizes that peripheral C3 is a promising target for the prevention and therapy, and a potential biomarker for predicting cognitive impairment, and confirms that the liver mediates anesthesia\/surgery\u2010induced cognitive impairment.<\/jats:p>","DOI":"10.1002\/advs.202502034","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T09:41:33Z","timestamp":1762940493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inhibiting Liver\u2010Derived C3 Protein Rescues Anesthesia\/Surgery\u2010Induced Cognitive Impairment, Synaptic Disorders, and Microglial Phagocytosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Qianqian","family":"Wu","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Clinical Research Center for Anesthesiology and Perioperative Medicine Translational Research Institute of Brain 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