Abstract
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 RIP-qPCR/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.