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

## TL;DR

This study shows that SIRT1 helps reduce cognitive issues in aging rats after anesthesia by regulating NAT10 and GABABR1, offering a new approach to prevent postoperative cognitive dysfunction.

## Contribution

The study identifies a novel SIRT1-NAT10-GABABR1 axis as a therapeutic target for anesthesia-induced cognitive impairment in aging.

## Key findings

- SIRT1 overexpression deacetylates NAT10, restoring autophagy and reducing oxidative stress in aged rats.
- NAT10 knockdown decreases Gababr1 expression and mitigates cognitive deficits caused by sevoflurane.
- SIRT1 reduces Baclofen-induced IPSC_slow via NAT10 deacetylation, normalizing synaptic inhibition.

## Abstract

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.

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.

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.

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.

The study reveals that NAT10 enhances GABABR1 mRNA stability via ac4A modification, leading to excessive inhibitory synaptic activation. In aged rats, sevoflurane contributes to cognitive impairment by inhibiting Sirt1 and neuronal autophagy, which subsequently disrupts energy metabolism.