Exploring the anti-diabetic potential of peimisine through bioinformatics analysis and <i>in vitro</i> studies

<h4>Ethnopharmacological relevance</h4><i>Fritillariae Cirrhosae Bulbus</i> is a traditional herb with diverse activities, yet its active metabolites against type 2 diabetes (T2D) remain unclear.<h4>Objective</h4>This study aimed to identify key bioactive metabolites from <i>Fritillariae Cirrhosae Bulbus</i> through database mining, and to evaluate the therapeutic potential of the selected metabolite peimisine against T2D through bioinformatics and experimental validation.<h4>Methods</h4>Metabolites were retrieved from TCMSP. Following ADME screening and literature validation, six metabolites were identified, from which peimisine was selected based on AlogP. Its targets were predicted using multiple databases, followed by GO and KEGG enrichment analyses and disease association analyses. Glucose uptake and gluconeogenesis assays were conducted in HepG2 cells, and key targets were further analyzed via PPI network and molecular docking.<h4>Results</h4>Six metabolites were identified, with peimisine selected as the most promising candidate. Bioinformatics analysis predicted 48 potential targets, with enrichment in metabolic pathways and a strong association with T2D. Experimentally, peimisine at 20 μM increased glucose uptake by up to 36.30% and reduced medium glucose by 57.65% under normal conditions; in an insulin-resistance model, it restored uptake by 42.82% and lowered glucose by 15.32%. It also significantly suppressed gluconeogenic enzymes, reducing PEPCK mRNA by 80% and G6PD by 31% relative to control. HSP90AA1 was identified as a central target, with a docking score of -7.9 kJ/mol.<h4>Conclusion</h4>Peimisine, a metabolite of <i>Fritillariae Cirrhosae Bulbus</i>, demonstrates anti-T2D potential by enhancing glucose uptake and suppressing gluconeogenesis, likely through targeting HSP90AA1, supporting its development as a phytotherapeutic candidate for T2D.