Integrative Multi-Omics Identifies S100A4 as a Translational Hub Linking Environmental Bis(2-Ethylhexyl) Phthalate (DEHP) Exposure to Glioblastoma Risk.

Glioblastoma (GBM) is a highly aggressive central nervous system malignancy with a dismal 5-year survival rate of less than 5%, and poorly understood environmental factors complicate its treatment. One such factor is bis(2-ethylhexyl) phthalate (DEHP, also known as di-2-ethylhexyl phthalate), a common plasticizer with documented neurotoxicity, yet its potential role in GBM pathogenesis remains elusive. In this study, we employed an integrative computational framework that combined network toxicology, single-cell transcriptomics, proteome-wide and metabolome-wide Mendelian randomization (MR), and molecular dynamics (MD) simulations to systematically investigate the interplay between DEHP and GBM risk. Cross-dataset targets were identified by mining toxicogenomic and disease databases, followed by the construction of a protein-protein interaction (PPI) network. This approach identified 76 overlapping targets between DEHP and GBM, which were refined to 24 hub genes through topological analysis. Notably, MR analyses revealed putative causal associations between higher genetically predicted plasma levels of three hub proteins-CD63, CTSS, and S100A4-and an increased risk of GBM, with S100A4 showing the strongest effect (odds ratio [OR] = 2.03, 95% confidence interval [CI] 1.15-3.58,