Aims: This study investigated how Sirtuin 1 (Sirt1) protects against sevoflurane- induced postoperative cognitive dysfunction (POCD) in aged rats by targeting N- acetyltransferase 10 (NAT10)- mediated mRNA acetylation and mitochondrial homeostasis. Methods: Aged rats received sevoflurane exposure and AAV- mediated Sirt1/Nat10 manipulation. We assessed autophagy (WB, LC3/TOM20 colocalization), energy metabolism (ROS/ATP, JC- 1), and Gababr1 expression (RT- qPCR, immunofluorescence). Cognitive function was evaluated using Y- maze, NORT, and MWM. scRNA- seq identified neuronal subpopulations, while RIPqPCR/ dot blot analyzed Nat10- Gababr1 mRNA interactions. Patch- clamp recordings measured IPSC_slow amplitudes. Results: Sevoflurane increased NAT10 expression and Gababr1 mRNA ac4C acetylation. Sirt1 overexpression deacetylated NAT10, restoring autophagy (↑LC3- II), reducing ROS, and improving cognition. scRNA- seq revealed SIRT1 enrichment in high- autophagy neurons. Nat10 knockdown decreased Gababr1 expression and cognitive deficits. Electrophysiology confirmed SIRT1- mediated reduction of Baclofen- induced IPSC_slow via NAT10 deacetylation. Conclusion: SIRT1 alleviates POCD by deacetylating NAT10 to reduce Gababr1 mRNA acetylation, thereby normalizing synaptic inhibition and restoring metabolic- autophagic balance. The SIRT1- NAT10- GABABR1 axis represents a novel therapeutic target for anesthesia- related neurotoxicity.
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