Exploring the Mechanism of Action of GLP-1RAs in the Treatment of Non-Alcoholic Fatty Liver Disease Combined with Diabetes Based on Network Pharmacology

目的：基于网络药理学探讨GLP-1RAs治疗非酒精性脂肪肝合并糖尿病的作用机制。方法：通过Pharmmapper、TargetNET、SEA和the Binding Database数据库查找筛选4种GLP-1RAs的作用靶点。通过GeneCards、DisGeNET以及OMIM查找并筛选NAFLD和T2DM的致病基因。使用DAVID数据库进行GO和KEGG富集分析，Cytoscape3.10.0绘制GLP-1RAs治疗NAFLD和T2DM的“药物–靶点–疾病的网络关系图”，利用MCODE插件进行聚类分析，Hubba插件筛选核心靶点，并绘制“核心靶点–通路的网络图”。结果：通过网络药理学筛选出GLP-1RAs治疗NAFLD合并T2DM的35个潜在靶点，筛选后获得13个核心靶点，它们分别是CASP3、ESR1、SIRT1、IGF1R、CCND1、GSK3B、AR、PRKACA、PARP1、NOS3、REN、MAPK8、ACE1。GO和KEGG富集分析结果表明，RAS系统相关通路和胰岛素抵抗相关通路是研究的关键通路。结论：GLP-1RAs有可能是通过激活RAS系统中ACE2/Ang(1-7)/Mas轴，对抗ACE/AngII/AT1R轴发挥其作用，以及根据血糖水平调节胰岛素的释放，增加胰岛素的生物合成和分泌等途径改善胰岛素抵抗对NAFLD和T2DM表现出有益疗效。Objective: To explore the mechanism of GLP-1RAs in the treatment of non-alcoholic fatty liver disease (NAFLD) complicated with type 2 diabetes mellitus (T2DM) through network pharmacology. Methods: The target proteins of four GLP-1RAs were screened via Pharmmapper, TargetNET, SEA and the Binding Database. The pathogenic genes of NAFLD and T2DM were retrieved and filtered through GeneCards, DisGeNET and OMIM. The DAVID database was employed for GO and KEGG enrichment analysis. Cytoscape3.10.0 was utilized to construct the “drug-target-disease network relationship diagram” for GLP-1RAs in treating NAFLD and T2DM. The MCODE plugin was used for cluster analysis, and the Hubba plugin was applied to screen core targets and create the “core target-pathway network diagram”. Results: Using network pharmacology, we identified 35 potential targets of GLP-1RAs for treating NAFLD with T2DM, and further screening yielded 13 core targets: CASP3, ESR1, SIRT1, IGF1R, CCND1, GSK3B, AR, PRKACA, PARP1, NOS3, REN, MAPK8, and ACE1. GO and KEGG enrichment analysis results indicate that pathways related to the RAS system and insulin resistance are critical pathways in the study. Conclusion: GLP-1RAs may exert their effects by activating the ACE2/Ang(1-7)/Mas axis in the RAS system to counteract the ACE/AngII/AT1R axis, and by regulating insulin release according to blood glucose levels, increasing insulin biosynthesis and secretion, and other pathways to improve insulin resistance, thereby showing beneficial effects on NAFLD and T2DM.