Targeting the SIRT1 ‐ NAT10 ‐ GABABR1 Axis: A Novel Epitranscriptomic Approach to Mitigate Sevoflurane‐Induced Cognitive Impairment in Aging

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.