Di(2-ethylhexyl) phthalate exposure: Association with metabolic associated steatotic liver disease and underlying mechanisms

Di(2-ethylhexyl) phthalate (DEHP) is a widely prevalent environmental pollutant that poses a threat to metabolic associated steatotic liver disease (MASLD). However, the specific mechanism remains unclear. This study combined the population data from the National Health and Nutrition Examination Survey (NHANES), and jointly employed network toxicology, molecular docking technology and in vitro cell experiments to establish a multi-dimensional research system of "population-network-molecule-cell". To clarify how DEHP interferes with the MASLD process. Our analysis based on NHANES data showed that DEHP exposure was significantly positively correlated with the risk of MASLD. Network toxicology identified 63 overlapping targets of DEHP and MASLD, and their functions were enriched in lipid metabolism, cytochrome P450-mediated drug metabolism and other pathway levels. Finally, five core targets (AKT1, ESR1, IL10, MMP9, PPARA) were identified. Molecular docking and molecular dynamics simulations indicated that these targets interacted with DEHP. In vitro experiments have shown that DEHP has the potential to induce lipid deposition in hepatocytes and have demonstrated the key role of the core targets. In conclusion, we showed that DEHP was closely related to MASLD through various dimensions. It was revealed that DEHP may regulate the occurrence and development of MASLD through multiple targets and pathways.