Mechanistic insights into Diuron-induced acute renal injury: Integration of network toxicology and experimental validation

Diuron is a widely used phenylurea herbicide known for its environmental persistence and potential health risks. While its hepatic and reproductive toxicities have been partly explored, its nephrotoxic effects remain insufficiently characterized. In this study, we employed an integrated approach combining network toxicology, molecular docking, transcriptomic analysis, and in vitro experiments to investigate the potential mechanisms of Diuron-induced AKI. We identified 149 overlapping targets between Diuron and AKI-related genes, with JAK2, STAT1, EGFR, NFKB1, and PARP1 highlighted as core genes through PPI network analysis. KEGG enrichment indicated significant involvement of the JAK-STAT signaling pathway and cancer-related pathways. Gene expression validation using the GSE145085 dataset and qPCR confirmed the involvement of these core genes in Diuron-induced AKI. Molecular docking confirmed stable binding between Diuron and the core proteins. Experimental validation in HK-2 cells revealed that Diuron significantly inhibited cell viability, proliferation, and migration in a dose-dependent manner, while activating phosphorylation of JAK2 and STAT1. These findings suggest that Diuron induces nephrotoxicity via activation of the JAK2/STAT1 pathway. This study offers novel mechanistic insights into the renal toxicity of Diuron and provides a scientific foundation for future toxicological risk assessment and preventive strategies related to environmental pesticide exposure.