Integrative m6A epitranscriptomic and transcriptomic analysis in livers of patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with hepatic metabolic remodeling, but the coordinated changes in N6-methyladenosine (m6A) modification and mRNA expression in human T2DM liver remain insufficiently defined. Here, we integrated mRNA expression profiles extracted from Arraystar Human LncRNA Microarray V5.0 with newly generated m6A epitranscriptomic microarray profiles in liver specimens from first-onset T2DM patients and controls. We identified 1923 differentially expressed and 7389 differentially m6A-methylated mRNA transcripts. Integrated analysis identified 898 dual-significant transcripts, predominated by hypermethylated-upregulated transcripts (n = 864), which were mainly enriched in amino acid, lipid, carbon, and energy metabolic pathways. By integrating m6A regulator expression, module-level correlation, and regulator-gene network connectivity, METTL14 was prioritized as a candidate component of the m6A writer complex associated with metabolic pathway remodeling. Ten METTL14-associated candidate genes were further prioritized, and clinical validation confirmed increased expression of METTL14 and most candidate genes in an independent human liver cohort. METTL14 depletion in Huh7 cells using two selected independent siRNAs concordantly reduced EHHADH, ACAT2, ACADS, SDHA, C3, and DLD. Secondary analysis of GSE185109 further showed significant downregulation of eight corresponding mouse orthologs in Mettl14-deficient liver, together with descriptive alterations in m6A peak patterns. These findings identify a functionally supported METTL14-associated m6A-mRNA network linked to hepatic metabolic remodeling in human T2DM, while direct transcript-specific m6A regulation remains to be established.