DEHP promotes psoriasis via immune modulation and direct molecular interactions: Evidence from epidemiology,...

Di (2-ethylhexyl) phthalate (DEHP), a widely used plasticizer with known immunotoxic effects, has been suspected of aggravating inflammatory skin conditions, yet its role in autoimmune diseases such as psoriasis remains poorly defined. In this study, we combined epidemiological analysis, systems biology, and molecular modeling to clarify this relationship. Using data from 1523 U.S. adults in NHANES 2009-2010, we found that individuals with psoriasis exhibited significantly higher urinary DEHP metabolite levels (P = 0.031) after adjusting for demographic and clinical covariates, providing the first population-level evidence for an association. To explore potential mechanisms, we integrated DEHP-binding protein predictions with psoriasis transcriptomic datasets and weighted gene co-expression analysis, identifying 365 overlapping genes enriched in TNF, calcium, AMPK, and HIF-1 signaling pathways. Machine learning approaches further prioritized 10 core genes with strong diagnostic performance (AUC > 0.85), whose expression correlated with altered immune cell infiltration in psoriatic lesions. Single-cell RNA sequencing localized these gene signatures to keratinocytes, T cells, and Langerhans cells, underscoring their relevance to skin immune regulation. Molecular docking confirmed stable interactions between DEHP and all core proteins, with strongest affinity for PAK3, and molecular dynamics simulations demonstrated sustained binding under physiological conditions. Collectively, our findings provide novel mechanistic insight into how environmental phthalate exposure contributes to psoriasis pathogenesis, advancing beyond prior animal-based studies and highlighting potential biomarkers and therapeutic targets for pollutant-driven autoimmune skin disease.