Mechanistic insights into DEHP-induced progression of non-small cell lung cancer based on network toxicology and molecular docking.

Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been implicated in various health risks, including tumorigenesis. Non-small cell lung cancer (NSCLC), accounting for over 80% of lung cancer cases, remains a leading cause of cancer-related mortality. This study employed network toxicology and molecular docking to explore the molecular mechanisms underlying DEHP's toxic effects on NSCLC. DEHP and NSCLC targets were retrieved from CTD, SwissTargetPrediction, and GeneCards, yielding 225 overlapping genes. Protein-protein interaction (PPI) network analysis identified five core targets: TP53, JUN, SRC, AKT1, and ESR1. Gene Ontology (GO) and KEGG pathway enrichment analyses revealed significant involvement of the PI3K/AKT signaling pathway and regulation of apoptotic signaling in DEHP-induced NSCLC pathogenesis. Molecular docking confirmed strong binding affinities between DEHP and the core targets, with binding energies ranging from - 4.611 to -7.535 kcal/mol. These findings suggest that DEHP promotes NSCLC progression, metastasis, and chemoresistance through PI3K/AKT signaling and apoptotic pathway dysregulation. This study provides mechanistic insights into DEHP's role in NSCLC and highlights the need for public health interventions to mitigate DEHP exposure. Further experimental validation is warranted to strengthen these findings and guide the development of targeted therapies.