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

Year: 2026

Type: article

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.

Source: CNS Neuroscience & Therapeutics

DOI: 10.1002/cns.70762

Authors: Xin Xie, Wei Du, Yanmei Zhang, Xiaomin Zhang

Institutions: Liaoning Cancer Hospital & Institute, China Medical University

Language: English

Topic: Anesthesia and Neurotoxicity Research

Subfield: Developmental Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,140