Network Toxicology Reveals the Mechanisms of the Plasticizer Metabolite MECPP in Metabolic Diseases

The degradation of plastic waste leads to the release of numerous chemical additives, including phthalate plasticizers, which have been implicated in the pathogenesis of metabolic disorders. Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer whose primary metabolite, mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), has been associated with multiple metabolic diseases. In this study, we applied an integrated approach combining network toxicology and molecular docking to systematically investigate the potential mechanistic role of MECPP in metabolic dysregulation. Our strategy included multi-platform target prediction, disease gene association analysis, functional enrichment, protein-protein interaction network construction, and molecular docking analysis. The results suggested that MECPP may be associated with six common core targets, including BCL2, BCL2L1, MAPK14, MMP2, MMP9, and TNFRSF1A, which are mainly involved in apoptosis, inflammatory regulation, and extracellular matrix remodeling. Pathway enrichment analysis further indicated the potential involvement of several disease-overlapping pathways, including insulin resistance, neuroactive ligand-receptor interaction, efferocytosis, advanced glycation end product-receptor for advanced glycation end product (AGE-RAGE) signaling, phospholipase D signaling, and renin secretion. Overall, these findings suggest that MECPP may contribute to metabolic dysregulation through overlapping molecular mechanisms across multiple diseases. This study provides a computational basis for future experimental validation and environmental risk assessment.