Integrative network toxicology, molecular dynamics and transcriptional analysis elucidate DEHP-induced cardiovascular dysfunction

Abstract Diethylhexyl phthalate (DEHP), a ubiquitous environmental pollutant, has been linked to cardiovascular diseases (CVDs), though the molecular mechanisms driving this association remain poorly understood. This study employed an integrated approach combining network toxicology, molecular docking, and molecular dynamics simulations to identify critical gene targets and elucidate their roles in DEHP-induced CVD pathogenesis. Potential clinical targets were screened using public databases (STITCH, ChEMBL, GeneCards, and OMIM), revealing ten core candidates: BCL2, IL6, KRAS, TNF, MAPK family members (MAPK1 and MAPK3), and cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP3A4, and CYP3A5). Molecular docking and dynamics simulations demonstrated stable interactions between DEHP and KRAS, TNF, MAPKs, and CYPs, suggesting direct functional modulation. In contrast, DEHP exhibited unstable binding with BCL2 and IL6. Notably, exposure to DEHP (50 μg/mL) significantly upregulated BCL2 and IL6 expressions. Given the close association of these genes with MAPK and TNF signaling pathways, their involvement in DEHP toxicity is likely indirect, mediated through pathway crosstalk. These findings advance our understanding of DEHP-induced cardiovascular dysfunction and highlight promising therapeutic targets for mitigating its adverse effects.