A network toxicology and molecular docking-based approach revealed shared hepatotoxic mechanisms and targets between the herbicide 2,4-D and its metabolite 2,4-DCP.

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and its major environmental metabolite 2,4-dichlorophenol (2,4-DCP) are pollutants associated with hepatotoxicity, whose molecular mechanisms remain poorly understood. This study investigated the molecular pathways and targets involved in 2,4-D and 2,4-DCP-induced hepatotoxicity using protein-protein interaction (PPI) network analyses and molecular docking. Target genes were identified using PharmMapper and SwissTargetPrediction, and cross-referenced with hepatotoxicity-related genes from GeneCards and OMIM databases. The PPI network, constructed via STRING and visualized in Cytoscape, revealed 12 critical hub nodes, including HSP90AA1, RXRA, EGFR, SRC, CREBBP, PIK3R1, ESR1, AKT1, RAF1, IGF1R, MDM2, and MAPK14. Gene Ontology (GO) analysis indicated processes such as apoptosis, oxidative stress, mitochondrial dysfunction, and lipid metabolism impairment, while Reactome pathway analysis highlighted disruptions in PI3K/AKT and nuclear receptors signaling. Molecular docking confirmed significant interactions of 2,4-D and 2,4-DCP with key proteins, including SRC, AKT, RXRA, MDM2, and HSP90AA1. These results suggest that 2,4-D and 2,4-DCP share similar toxic mechanisms, providing new insights into their hepatotoxicity pathways for the first time.