Molecular mechanism of Ginkgo biloba in treating type 2 diabetes mellitus combined with non‐alcoholic fatty liver disease based on network pharmacology, molecular docking, and experimental evaluations

Ginkgo biloba has gained increasing attention owing to its remarkable effects against cardiovascular disease. However, the role of G. biloba in hepatic lipid metabolism disorders in type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms have not been elucidated. Here, the effective ingredients and mechanisms of action of G. biloba in T2DM combined with NAFLD were investigated via an integrated strategy of network pharmacology and molecular docking. Thirty-four core targets for the alleviation of T2DM combined with NAFLD were identified and retrieved from multiple open-source databases, after validating the ameliorative effect of G. biloba on lipid accumulation in vitro. The targets IL6, IL1B, VEGFA, PTGS2, and CCL2, among others, with high network association values, were screened using Cytoscape. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that 34 compounds derived from G. biloba may exert therapeutic effects via response to molecule of bacterial origin, cellular response to lipid, and response to the hormone. In addition, the AGE-RAGE and IL-17 signaling pathways were predicted to be most significantly affected. Meanwhile, the outcomes of the molecular docking experiment showed that the most effective ingredients in G. biloba showed a strong binding affinity to the potential target active sites. Findings from further in vitro experiments confirmed that G. biloba treatment decreased the level of IL6, IL1B, and VEGFA protein. In conclusion, our findings provided novel insights into the mechanisms underlying the therapeutic effect of G. biloba in T2DM combined with NAFLD. PRACTICAL APPLICATIONS: As a medicinal food plant, G. biloba has been shown to exert benefits in cardiovascular diseases. However, the pharmacological material basis and complex mechanism of action in G. biloba in T2DM combined with NAFLD remain unknown. Here, the mechanism by which G. biloba could ameliorate T2DM combined with NAFLD was investigated, and the potential target and molecular mechanism were explored, through a comprehensive strategy combining network pharmacology and molecular docking. Our findings indicate that G. biloba exerts synergistic effects in treating T2DM combined with NAFLD through multi-ingredients, multi-targets, and multi-pathways; the findings also elucidate the nutritional and therapeutic potential of G. biloba in preventing and treating T2DM combined with NAFLD and provides robust evidence for its clinical application.