Integrative Multi-Analysis Identifies METTL3-Regulated FGF19 and H6PD as Candidate Targets in Diabetic Cognitive...

Diabetic cognitive impairment (DCI) is a serious and growing public health concern. The role of N6-methyladenosine (m⁶A), the predominant mRNA modification in the mammalian brain, in DCI pathogenesis remains not fully elucidated. Here, GEO-derived diabetes datasets were combined with in vivo and in vitro models to reveal aberrant expression of m⁶A-related genes. The results showed that the overall level of m⁶A RNA methylation in both the diabetic group and the high-glucose group was significantly decreased compared to the normal group. In addition, the expression of methyltransferase METTL3, which is involved in the regulation of m⁶A RNA methylation, was downregulated in both diabetic and hyperglycemic groups, and was positively correlated with the downregulation of the overall m⁶A level. Neuronal models with stable METTL3 knockdown were generated using lentiviral transduction. Subsequent ¹H-NMR metabolomic and MeRIP-qPCR analyses demonstrated that METTL3 deficiency disrupts key metabolic pathways, including phosphatidylethanolamine and phosphatidylcholine biosynthesis and glucose-alanine metabolism, and identified Fgf15 (the mouse ortholog of human FGF19) and H6PD as candidate downstream targets. Collectively, these data suggest that METTL3-dependent m⁶A RNA methylation alterations may contribute to DCI through metabolic dysregulation, positioning METTL3 as a promising therapeutic target for DCI.