A novel metabolic gene signature induced by Di-(2-ethylhexyl) phthalate and Mono-(2-ethylhexyl) phthalate exposure predicts prognosis in breast cancer: An integrative bioinformatics and experimental study

Di-(2-ethylhexyl) phthalate (DEHP) and its metabolite mono-(2-ethylhexyl) phthalate (MEHP) are endocrine-disrupting chemicals linked to breast cancer progression, yet the underlying prognostic mechanisms are poorly elucidated. This study employed a bioinformatics approach, integrating computational target prediction, protein-protein interaction (PPI) network analysis, and transcriptomic data from The Cancer Genome Atlas (TCGA), to identify prognostic genes modulated by DEHP/MEHP. Through Cox and LASSO regression, we identified a novel gene signature primarily involved in lipid metabolism (PPARD, CPT1A, LPCAT1, AGPAT1,PLIN5) and mitochondrial complex I (NDUFAB1, NDUFV1, NDUFAF4, MT-ND1), which was associated with patient survival. Molecular docking and dynamics simulations were performed to assess the binding affinity between DEHP/MEHP and core targets, confirming stable, high-affinity interactions. In vitro experiments further showed that DEHP and MEHP promote the proliferation and migration of breast cancer cells (MCF-7 and MDA-MB-231), enhance lipid accumulation and mitochondrial function, and validate the altered expression of these prognostic genes at the transcriptional level, with MEHP exerting more pronounced effects. In conclusion, this study suggests that DEHP and MEHP may activate metabolic reprogramming in breast cancer, thereby contributing to disease progression and poorer prognosis, highlighting these genes as potential prognostic biomarkers and therapeutic targets. • Identification of a novel DEHP/MEHP-regulated gene signature linked to breast cancer prognosis. • Lipid metabolism and mitochondrial gene upregulation correlated with poor survival in breast cancer. • In vitro experiments show DEHP/MEHP exposure promotes breast cancer cell proliferation and migration. • Molecular docking and dynamics simulations suggest DEHP/MEHP-PPARD interaction with potential activating effect. • RT-qPCR validation confirms differential expression of key genes in breast cancer tissues.