Network toxicology study and key target validation of chlorpyrifos-induced nonalcoholic fatty liver disease

Chlorpyrifos (CPF) is a widely used insecticide known for its extended persistence in soil and water. It can induce non-alcoholic fatty liver disease (NAFLD) in mice. However, the specific molecular mechanisms responsible for CPF-induced NAFLD remain partially understood. Utilizing network toxicology analysis, we have identified TP53, HSP90AA1, AKT1, and JUN as pivotal driver genes orchestrating NAFLD progression triggered by CPF. A predictive nomogram constructed on these core genes demonstrates promising translational prospects for NAFLD. Gene-set enrichment analysis (GSEA) underscores the significance of the tricarboxylic acid (TCA) cycle and histidine metabolism as critical pathways associated with CPF-induced NAFLD. Evaluation of immune infiltration patterns reveals notable changes in the immunological milieu and accelerated disease advancement in CPF-induced NAFLD. Molecular docking and dynamic simulations provide support for the formation of stable complexes between CPF and proteins encoded by the identified core genes. Ultimately, biomedical experiments confirmed that CPF exacerbates the pathological progression of NAFLD by stabilizing HSP90AA1 protein and promoting the phosphorylation of TP53 and JUN. This study elucidates the molecular mechanisms underpinning CPF-induced NAFLD, providing a theoretical foundation for comprehending its pathogenesis.