OBJECTIVE  This study aims to elucidate the mechanism of action of Isoliquiritigenin (ILG) in the treatment of Diabetic Encephalopathy (DE) based on network pharmacological analysis and in-vitro experiments.

  METHODS  The potential targets of ILG were predicted using the HERB database and SwissTargetPrediction database. DE-associated disease targets were obtained from GeneCards, OMIM, and PharmGkb, and the intersecting targets between ILG and DE were identified using the Venny software. A PPI network was constructed using the STRING database, and core targets were screened out using Cytoscape software. GO function and KEGG pathway enrichment analyses were undertaken using R 4.0.3, followed by validation via molecular docking techniques and in vitro experiments.

  RESULTS  65 intersecting targets between ILG and DE were identified in this study. Topological analysis yielded eight core targets namely, EGFR, ESR1, PTGS2, PPARG, GSK3β, CDK2, PIK3R1, and F3. GO function and KEGG pathway enrichment analyses revealed that ILG antagonizes DE through several biological processes which impact numerous cellular components and molecular functions such as response to lipopolysaccharides, protein phosphorylation, protein kinase activity, and serine/threonine/tyrosine kinase activity. Pathways implicated included the PI3K-Akt signaling pathway, protein polysaccharide signaling pathway in cancer, and endocrine resistance pathway. The molecular docking results showed that all eight core targets had a good binding with ILG, especially with GSK3β, with a binding energy of -7.22 kcal·mol^-1. In vitro experiments indicated that ILG could improve high glucose-induced cell damage and activate the PI3K/AKT/GSK3β signaling pathway.

  CONCLUSION  ILG is likely to exert its effects on GSK3β to regulate the PI3K/AKT/GSK3β signaling pathway, thereby alleviating DE.