Integrative Network Pharmacology, Molecular Docking, and In-Vitro Analysis of the Antidiabetic Potential of Diosmin

Background: Diosmin, a citrus-derived flavonoid, exhibits antioxidant, anti-inflammatory and metabolic regulatory properties; however, its molecular mechanisms and multitarget interactions in diabetes mellitus remain poorly understood and not fully clear. Methods: An integrative strategy combining network pharmacology, molecular docking and in vitro enzyme inhibition assays were employed in this study. Diosmin-associated targets were retrieved from the Comparative Toxicogenomics Database (CTD; accessed January 2025) and intersected with diabetes mellitus–related genes obtained from GeneCards (version 5.18; relevance score ≥10). Protein–protein interaction (PPI) networks was constructed using STITCH (confidence score ≥0.08) and analyzed by Cytoscape (version 3.9.1). Gene Ontology (GO) and KEGG pathway enrichment analysis were performed using g: Profiler. Molecular docking was conducted using AutoDock Vina against key insulin-signaling proteins including insulin receptor (IR), insulin receptor substrate-1 (IRS-1), PI3K, AKT1 and GLUT4. In vitro α-amylase and α-glucosidase inhibition assays were performed, using acarbose as the reference drug. Results: Network pharmacology analysis identified 39 common targets, which are primarily involved in insulin signaling, AMPK signaling and glucose metabolism pathways although some overlap existed. The ADME profile supports diosmin as a safe and pharmacologically relevant nutraceutical or lead compound rather than a conventional orally bioavailable small molecule drug. Docking analysis suggested favorable binding propensities of diosmin toward selected hub proteins, ranging from −9.3 to −11.3 kcal/mol; with GLUT4 and PI3K showing the highest affinities among the targets. In vitro assays demonstrated dose-dependent inhibition of α-amylase and α-glucosidase by diosmin, although it was less potent when compared than acarbose. Conclusion: Diosmin may have potential antidiabetic property through multitarget modulation of insulin signaling and carbohydrate-hydrolyzing enzymes, suggesting a systems-level mechanism. A limitation of this study is the absence of cellular and in vivo validation which may affect interpretation, warranting further experimental confirmation in future studies