Integrated network toxicology, molecular docking and transcriptomics reveal the mechanistic role of phthalate esters in metabolic disease pathogenesis

Phthalate ester plasticizers (PAEs), common environmental pollutants, are linked to metabolic disorders like obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH), but their multi-target molecular mechanisms remain unclear. This study integrated network toxicology, transcriptomics, molecular docking, and molecular dynamics simulations to explore metabolic toxicity mechanisms of three common PAEs, including diethyl phthalate (DEP), dimethyl phthalate (DMP), and di-n-octyl phthalate (DNOP). A "plasticizer-target-disease" network was constructed, binding interactions assessed via molecular docking, and transcriptomes of DEP-exposed adipocytes and hepatocytes analyzed. Common targets of the three PAEs intersecting with diseases enriched in metabolism-related pathways. PPI network identified IL6, PPARG, BCL2, and CASP3 as core targets, with stable binding confirmed by molecular assays. Transcriptomic data showed DEP disrupts metabolic pathways in adipocytes and hepatocytes. Our findings suggest PAEs may promote metabolic diseases via the PPARG-IL6-BCL2-CASP3 axis, activating lipid accumulation-inflammation-apoptosis-fibrosis cascades. This study not only reveals the potential mechanistic link between plasticizers exposure and metabolic dysfunction, but also demonstrates the utility of network toxicology, molecular docking, and molecular dynamics simulation in evaluating the toxicity of environmental pollutants, laying a theoretical foundation for intervention targets, risk assessment, and prevention strategies.

MASH; MASLD; Metabolic homeostasis; Network toxicology; Obesity; Phthalate esters.