Exploring the Molecular Mechanisms Underlying the Comorbidity of Type 2 Diabetes Mellitus and Nonalcoholic Steatohepatitis: A Bioinformatics Analysis

Abstract Investigating the comorbidity mechanisms of Type 2 Diabetes Mellitus (T2DM) and Non-Alcoholic Steatohepatitis (NASH) using bioinformatics analysis. T2DM and NASH are significant global health challenges, often coexisting and exacerbating each other's pathophysiology. Our study aims to elucidate the underlying mechanisms linking these two conditions by identifying common differentially expressed genes (DEGs) and microRNAs (miRNAs) through the analysis of publicly available gene expression datasets from the Gene Expression Omnibus (GEO). Methods: Gene expression datasets related to T2DM and NASH were retrieved from GEO. Differentially expressed genes were identified using the GEO2R tool, and common DEGs were determined through Venn diagram analysis. Functional enrichment analysis was performed using the R package "clusterProfiler," and protein-protein interaction (PPI) networks were constructed using STRING. Hub genes were identified using Cytohubba in Cytoscape. Transcription factors (TFs) were predicted using the TRRUST database, and common miRNAs were identified using the R package "edgeR" and GEO2R. The miRNAs-mRNAs regulatory network was established by integrating common DEGs and predicted miRNAs. Results: A total of 129 common DEGs were identified, including 20 downregulated and 109 upregulated genes. Enrichment analysis revealed that these DEGs were involved in biological processes such as peptidyl-serine modification, RNA splicing, and cellular response to nutrient levels. Nine hub genes were identified: MAPK1, U2AF1, SNRNP70, ZC3H13, TAF15, SMARCA4, HNRNPD, SRSF3, and SRSF11. These genes were associated with pathways related to RNA splicing, and metabolic regulation. Six common miRNAs (hsa-miR-361-5p, hsa-miR-520e, hsa-miR-320b, hsa-miR-595, hsa-miR-610, and hsa-miR-498) were identified, which were involved in cell cycle regulation, angiogenesis, and inflammation. The miRNAs-mRNAs network showed interactions between these miRNAs and three important genes: SRSF3, HNRNPD, and ZC3H13. Conclusion our study provides insights into the comorbidity mechanisms of T2DM and NASH through bioinformatics analysis. The identified hub genes and miRNAs offer potential therapeutic targets for future research.