Identifying key molecular interactions and pathways linking DEHP and its metabolite MEHP to allergic rhinitis: a network toxicology and molecular dynamics study

Di-(2-ethylhexyl) phthalate (DEHP) and its major metabolite mono-(2-ethylhexyl) phthalate (MEHP) are ubiquitous environmental contaminants increasingly implicated in allergic rhinitis (AR). However, their molecular mechanisms remain unclear. This study aimed to employ a computational toxicology approach to predict DEHP/MEHP-associated toxicological targets and pathways relevant to AR and to screen for key mediators underpinning this association. Putative targets of DEHP and MEHP were compiled using SEA, SwissTargetPrediction, and TargetNet, while AR-related genes were curated from GeneCards, DrugBank, OMIM, DisGeNET, and PharmGKB. After deduplication, overlapping targets were analyzed via STRING-based protein–protein interaction (PPI) networks and GO/KEGG enrichment. Specifically, unique targets common to DEHP, MEHP, and AR were identified and prioritized. Expression of the core target was evaluated in the GSE52804 dataset (OVA-induced AR mouse model). Molecular docking assessed binding of DEHP/MEHP to PTGS2, followed by molecular dynamics (MD) simulations and free energy landscape (FEL) analyses. We identified 370 unique predicted targets of DEHP/MEHP and 1,213 genes associated with AR, yielding 71 overlapping genes. Functional enrichment analysis of these overlaps suggested their potential involvement in inflammatory and immune pathways. Among these, 21 targets common to DEHP, MEHP, and AR were predicted to be associated with key biological processes such as cellular response to environmental stimulus. PPI network topology analysis indicated PTGS2 as a central hub gene. Molecular docking predicted moderate affinity for both ligands, with scores of − 6.4 for DEHP and − 7.6 for MEHP to PTGS2. MD simulations demonstrated the stability of both predicted complexes, with consistent binding free energies and the presence of persistent hydrogen bonds. FELs showed well-defined global minima for both complexes. This in silico analysis predicts potential multi-target interactions between DEHP/MEHP and proteins implicated in AR pathogenesis. Among these, PTGS2 emerged as a high-priority candidate based on network topology and molecular docking evaluations. The computational results identify PTGS2 and other hub targets as candidates for experimental validation in the context of DEHP/MEHP exposure.