• Vaccarin (VAC) improves renal function and mitigates histological damage in a mouse model of type 2 diabetic nephropathy (DN).
• VAC inhibits renal fibrosis, inflammation, oxidative stress, and epithelial-mesenchymal transition (EMT) in diabetic kidneys and high glucose-induced HK-2 cells.
• Network pharmacology and molecular docking identify EGFR as a direct target of VAC, with binding mediated by Lys-879, Ile-918, and Ala-920.
• VAC suppresses the EGFR/ERK1/2 signaling pathway, and blocking either EGFR or ERK1/2 mimics its renal benefits, suggesting a novel therapeutic strategy for DN.