The Integration of Metabolites from and Gut Microbiota Ameliorates Drug-induced Liver Injury: Network Pharmacology and Molecular Docking Studies

This study integrates metabolites from Forsythia suspensa (FS) and gut microbiota GM to assess combined therapeutic efficacy against drug-induced liver injury (DILI) using network pharmacology and molecular docking. Metabolites of FS and GM were retrieved from the NPASS and gutMGene databases, respectively. Relevant targets for metabolites and DILI-related targets were identified through public databases. The PPI network and KEGG pathway analysis were employed to identify hub targets and key signalling pathways. Furthermore, we performed a molecular docking assay on the active metabolites and targets to verify the network pharmacological concept. The physicochemical properties and toxicity of identified key metabolites were assessed using in silico platforms. 19 final targets were recognized as key proteins responsible for the alleviation of DILI by FS and GM metabolites, with ESR1 emerging as a central target in the PPI network. The estrogen signalling pathway, particularly involving ESR1, ESR2 and JUN genes, was identified as a key mediator in the therapeutic effects. Four GM metabolites (baicalein, luteolin, lunularin and 2,3-bis(3,4-dihydroxybenzyl)butyrolactone) and two FS metabolites (pinoresinol and isolariciresinol) were identified as non-toxic, promising candidates. In conclusion, metabolites from FS and GM may exert a potent synergistic effect on DILI through modulation of the estrogen signalling pathway.