The role of N6-methyladenosine associated genes in ischemic stroke risk: interplay with environmental factors

Ischemic stroke is a leading cause of morbidity and mortality worldwide, resulting from a complex interplay between genetic predisposition and environmental exposures. Recent advances have highlighted the importance of epitranscriptomic regulation, particularly N6-methyladenosine (m⁶A) RNA modification, in the pathogenesis of cerebrovascular diseases. Key m⁶A‑related genes, including the demethylases FTO and ALKBH5, the methyltransferase complex components METTL3 and METTL14, and m⁶A readers of the YTH domain family (e.g., YTHDF1, YTHDF2, YTHDC1), have been implicated in processes such as vascular homeostasis, neuroinflammation, and neuronal survival. Emerging evidence suggests that specific genetic variants within these genes (for e.g., FTO rs9939609, FTO rs17817449, ALKBH5 rs12936694, METTL3 rs1139130, and YTHDF/ YTHDC locus polymorphisms) may modulate individual susceptibility to ischemic stroke. In a real-world contexts, lifestyle and environmental exposures such as diet, smoking, physical activity, and air pollution may interact with these genetic factors, potentially modifying overall stroke risk. This is the first review to systematically highlight m6A-related genes as key interfaces linking genetic susceptibility with environmental exposures in ischemic stroke, emphasizing their potential role as dynamic environmental sensors translating exposure signals into transcriptional and phenotypic outcomes. Elucidating these complex interactions could inform strategies for stroke prevention and the development of personalized therapeutic approaches.