Propofol regulates SLC6A2 expression via NAT10-mediated ac4C modification to modulate excessive mitophagy and...

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and propofol exposure has been implicated in its pathogenesis. This study investigated whether propofol exacerbates hippocampal neuron dysfunction via N4-acetylcytidine (ac4C) modification mediated by N-acetyltransferase 10 (NAT10). HT22 cells were treated with propofol to assess cytotoxicity, inflammation, oxidative stress, and mitophagy. The NAT10/SLC6A2 interaction was validated using ac4C RNA immunoprecipitation (RIP), RNA pull-down, and dual-luciferase reporter assays. A POCD model was established by tibial fracture surgery in C57BL/6 J mice. Cognitive function was evaluated using Morris water maze and Y-maze tests. Propofol treatment upregulated SLC6A2 and NAT10 expression in HT22 cells (P < 0.05). Knockdown of SLC6A2 attenuated propofol-induced cytotoxicity, apoptosis, inflammation, oxidative stress, mitochondrial depolarization, and excessive mitophagy (P < 0.05). Mechanistically, NAT10 directly bound to SLC6A2 mRNA and induced ac4C modification of SLC6A2 mRNA, enhancing its stability. Overexpression of SLC6A2 reversed the protective effects of NAT10 knockdown (P < 0.05). In addition, the NAT10/SLC6A2 axis mediated propofol-induced activation of the NF-κB pathway (P < 0.05). In aged POCD mice, knockdown of SLC6A2 improved cognitive performance and reduced neuroinflammation, oxidative stress, and excessive mitophagy (P < 0.05). Propofol promotes excessive mitophagy and hippocampal neuron dysfunction in aged POCD via the NAT10-mediated ac4C modification-dependent upregulation of SLC6A2. Targeting SLC6A2 may represent a potential therapeutic strategy for POCD.