Based on network pharmacology to explore the mechanism of hepatotoxicity of Fructus Meliae Toosendan

Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database,PubChem Database and Swiss Target Prediction database,etc.Genecards,pharmGKB,and OMIM databases were used to collect relevant targets of hepatotoxicity,and intersect them with the targets of active ingredients to obtain the potential targets of hepatotoxicity caused by FMT.A compound-target network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted by R software,and then the pathways directly related to hepatotoxicity were integrated.Results:In this study,9 active ingredients of FMT and 265 targets were obtained.There are 533 hepatotoxicity-related targets,and 76 potential targets for hepatotoxicity caused by FMT,among which quercetin,melianone,and nimbolin A are the key active components for hepatotoxicity caused by FMT,and MYC,STAT3,JUN,and RELA were the core target proteins of FMT’s hepatotoxicity.There were 2353 GO entries(P<0.05),including 2181 Biological Process(BP),41 Cellular Component(CC)and 131 Molecular Function(MF).KEGG enrichment analysis revealed 165 pathways(P<0.05),of which Th17 cell differentiation,HIF-1 signaling pathway,PI3K-Akt signaling pathway were strongly correlated with the hepatotoxicity of FMT.Conclusion:Through network pharmacology,it was found that many potential components in azadirachia chinaberry may be involved in the regulation of apoptosis,excessive inflammatory response and mitochondrial dynamics through multi-target and multi-pathway,resulting in the generation of hepatotoxicity.