Epigenetic regulation in cognitive impairment: Focus on N6-methyladenosine modification and its potential role in...

N6-methyladenosine (m6A), the most abundant internal modification in mammalian mRNA, plays a critical role in cognitive function by dynamically regulating gene expression. This narrative review examines m6A's role in cognitive processes and its potential impact on perioperative neurocognitive disorders (PNDs), which encompass a spectrum including postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction. The m6A regulatory machinery-comprising methyltransferases ("writers"), demethylases ("erasers"), and recognition proteins ("readers")-modulates neuronal development, synaptic plasticity, and cognitive processes by influencing mRNA stability, translation, and degradation. Evidence from animal models indicates that m6A dysregulation contributes to neuroinflammation, neurodegeneration, and neuronal injury, which are pathophysiological mechanisms implicated in PNDs. Notably, anesthetic agents and surgical stress have been shown to alter hippocampal m6A levels, and manipulation of m6A-related proteins may ameliorate cognitive deficits. While these findings suggest potential mechanistic connections, direct evidence specifically linking m6A modifications to PNDs pathogenesis remains preliminary and largely based on preclinical models. Further research is needed to establish causal relationships, identify m6A-modified targets relevant to PNDs pathology, and evaluate m6A as a potential biomarker or therapeutic target. This review provides a foundation for understanding how m6A modification may influence perioperative cognitive outcomes and identifies promising avenues for future investigation.