Inhibiting Liver‐Derived C3 Protein Rescues Anesthesia/Surgery‐Induced Cognitive Impairment, Synaptic Disorders, and Microglial Phagocytosis

This study provides evidence that anesthesia/surgery can induce the BBB breakdown 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, which results in structural and functional injury of synapse, C3aR‐mediated microglial phagocytosis, and cognitive impairment. Abstract Identifying peripheral proteins having therapeutic effects on cognitive impairment could provide beneficial insights into the prevention and treatment of cognition‐related disorders, including postoperative cognitive dysfunction (POCD) that is a common postoperative cognitive impairment mainly caused by anesthesia/surgery. Here, proteomic and transcriptomic analyses in multiple organs from humans and POCD mice are conducted to identify potential peripheral targets for anesthesia/surgery‐induced cognitive impairment. The results show that anesthesia/surgery can disrupt the blood‐brain 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‐induced C3 upregulation in the liver is associated with hypomethylation of C3 promoter. Inhibiting hepatogenous C3 is demonstrated to salvage the anesthesia/surgery‐induced cognitive impairment, structural and functional injury of synapse, and C3aR‐mediated 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‐induced cognitive impairment. This study provides evidence that anesthesia/surgery can induce the BBB breakdown 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, which results in structural and functional injury of synapse, C3aR-mediated microglial phagocytosis, and cognitive impairment. Abstract Identifying peripheral proteins having therapeutic effects on cognitive impairment could provide beneficial insights into the prevention and treatment of cognition-related disorders, including postoperative cognitive dysfunction (POCD) that is a common postoperative cognitive impairment mainly caused by anesthesia/surgery. Here, proteomic and transcriptomic analyses in multiple organs from humans and POCD mice are conducted to identify potential peripheral targets for anesthesia/surgery-induced cognitive impairment. The results show that anesthesia/surgery can disrupt the blood-brain 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-induced C3 upregulation in the liver is associated with hypomethylation of C3 promoter. Inhibiting hepatogenous C3 is demonstrated to salvage the anesthesia/surgery-induced cognitive impairment, structural and functional injury of synapse, and C3aR-mediated 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-induced cognitive impairment. Advanced Science, Volume 13, Issue 2, 9 January 2026.