Network Pharmacology to Reveal the Molecular Mechanisms of Rutaceous Plant-derived Limonin Ameliorating Non-alcoholic Steatohepatitis.

ABSTRACT

BACKGROUND: Limonin shows promise in alleviating non-alcoholic fatty liver disease. We investigated the mechanisms of limonin against non-alcoholic steatohepatitis (NASH) using network pharmacology and molecular docking. METHODS: Public databases provided NASH- and limonin-associated targets. VennDiagram identified potential limonin targets for NASH. Enrichment analysis explored the limonin-NASH relationship. PPI network analysis, CytoHubba models, and bioinformatics identified hub genes for NASH treatment. Molecular docking assessed limonin's binding ability to hub targets. RESULTS: We found 37 potential limonin targets in NASH, involved in oxidative stress, inflammation, and signaling pathways. PPI network analysis revealed seven hub genes (STAT3, NFKBIA, MTOR, TLR4, CASP8, PTGS2, NFKB1) as NASH treatment targets. Molecular docking confirmed limonin's binding to STAT3, CASP8, and PTGS2. Animal experiments on high-fat diet mice showed limonin reduced hepatic steatosis, lipid accumulation, and expression of p-STAT3/STAT3, CASP8, and PTGS2. CONCLUSION: Limonin's therapeutic effects in NASH may stem from its antioxidant and anti-inflammatory properties. STAT3, CASP8, and PTGS2 are potential key targets for NASH treatment, warranting further investigation.