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

## TL;DR

This study explores how reduced METTL3 activity, linked to RNA methylation, may contribute to diabetic cognitive impairment by disrupting key metabolic pathways.

## Contribution

The study identifies FGF19 and H6PD as novel candidate targets downstream of METTL3 in diabetic cognitive impairment.

## Key findings

- Reduced m6A RNA methylation levels were observed in diabetic and high-glucose groups.
- METTL3 knockdown disrupted metabolic pathways like phosphatidylethanolamine biosynthesis and glucose–alanine metabolism.
- Fgf15 (mouse ortholog of FGF19) and H6PD were identified as potential downstream targets of METTL3.

## Abstract

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.