Investigating the Anti-Diabetic and Renoprotective Potential of Diosgenin Using Computational Chemistry, Molecular Docking, and Experimental Validation

Diabetic Nephropathy (DN) is a major cause of End-Stage Renal Disorder (ESRD) globally and a serious complication of Diabetes Mellitus (DM). The need for effective therapies remains critical. This study explores the therapeutic potential of diosgenin against DN and investigates the mechanisms underlying its renoprotective effects. The ADME profile of Diosgenin was predicted with SwissADME. Potential targets were retrieved via SwissTargetPrediction and Super-PRED, and diabetic nephropathy targets from GeneCards; overlaps were visualized in Venny 2.1. A PPI network was built in STRING (score >0.4) and analyzed in Cytoscape 3.10.2 with CytoHubba. GO and KEGG enrichment of shared targets was performed in DAVID and presented using bioinformatics visualization tools. Molecular docking of diosgenin with NF-κB (1NFI), STAT3 (6NUQ), and PTGS2 (1CX2) was done in CB-Dock2; binding interactions were examined in BIOVIA Discovery Studio. In vivo, STZ-induced diabetic nephropathy was modelled in Wistar rats; diosgenin (20 mg/kg/day, orally, 8 weeks) effects were assessed by OGTT, kidney GSH, SOD, lipid peroxidation assays, TNF-α and IL-1β ELISAs, and Western blotting for NFKB1, STAT3, and PTGS2. Diosgenin showed high GI absorption, BBB permeability, a bioavailability score of 0.55, and no major toxicity. Of 70 compound targets and 2,025 disease targets, 56 overlapped. The PPI network comprised 56 nodes and 858 edges; hub genes were NFKB1 (degree 53), STAT3 (52), PTGS2 (51). GO terms enriched included protein kinase regulation, ROS metabolism, and nuclear receptor activity; KEGG pathways encompassed AGE-RAGE, insulin resistance, and PI3K-Akt signaling. Docking yielded Vina scores of –11.9 (PTGS2), –9.1 (NF-κB), and –7.7 (STAT3), reflecting favorable interactions. In vivo, diosgenin improved OGTT, elevated GSH and SOD, reduced lipid peroxidation, and lowered TNF-α and IL-1β versus untreated diabetic rats. Western blot confirmed dose-dependent downregulation of NFKB1, STAT3, and PTGS2 in renal tissue. The study provides convincing evidence, based on network pharmacology and experimental validation, for the renoprotective effects of diosgenin in diabetic nephropathy.