Integrated network toxicology and molecular docking revealed that 2-ethylhexyldiphenylphosphoric acid induces nephrotoxicity in chickens by activating the ROS/JNK pathway.

2-Ethylhexyl diphenyl phosphate (EHDPHP) is a widely used novel organophosphorus flame retardant. In recent years, EHDPHP has been absorbed into humans and animals through contaminated environments and food intake, causing substantial adverse effects. Therefore, the biological toxicity of EHDPHP has aroused widespread interest among researchers. However, research on the toxic damage mechanism of EHDPHP on the kidneys of poultry is still relatively limited. This study predicted the target sites of EHDPHP through network toxicology and molecular docking. Subsequently, chickens were administered varying concentrations of EHDPHP by oral gavage, and kidney tissues were collected on days 14, 28 and 42 to elucidate its potential nephrotoxic mechanism. Network biology analysis indicates that the predicted targets of EHDPHP and its critical metabolite 5-OH-EHDPHP are significantly enriched in MAPK and apoptotic pathways. The results of molecular docking showed that both EHDPHP and 5-OH-EHDPHP had good binding ability with JNK1/2, suggesting that JNK1/2 was a potential target for EHDPHP. Experimentally, EHDPHP exposure was found to induce oxidative stress, mitochondrial damage and apoptosis in chicken kidneys. These results suggest that kidney injury may be mediated through the activation of the ROS/JNK signaling pathway and the subsequent triggering of apoptosis. In conclusion, our study offers a foundation for further toxicological evaluation and mechanistic investigation of contaminant EHDPHP.