Exploring the Key Targets and Underlying Mechanisms of Brain Injury Induced by the Plasticizer DEHP through Network Toxicology and Molecular Docking Approaches

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer with documented neurotoxic effects, posing significant risks to brain tissue development and function. However, its precise molecular mechanisms and toxicological networks remain incompletely understood. This study aimed to elucidate the molecular mechanisms underlying DEHP-induced brain damage through network toxicology and molecular docking approaches. Public databases, including ChEMBL, STITCH, GeneCards, TTD, and OMIM, were used to construct the intersection network of DEHP-related targets and brain injury targets. Key pathways were identified via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Core targets were further screened using STRING and Cytoscape tools. To evaluate the diagnostic value of these core targets in brain injury, a logistic regression-based diagnostic model was developed, and a nomogram was constructed. The diagnostic performance and predictive accuracy of the nomogram were assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Immune cell infiltration in brain-injured and non-brain-injured cohorts was analyzed using the CIBERSORT method, and the correlation between core genes and immune cells was explored. Molecular docking techniques were employed to validate the binding affinities of DEHP to the core targets. The findings revealed KRAS, BCL2, EGFR, CCND1, CASP3, IL6, HSP90AA1, and ESR1 as pivotal targets of DEHP-induced brain injury. Enrichment analyses suggested that DEHP aggravates brain damage by disrupting cell survival, inflammation, apoptosis, and oxygen homeostasis. Key implicated pathways included the PI3K-Akt, JAK-STAT, FoxO, TNF, and HIF-1 signaling pathways. The nomogram model incorporating these eight core targets demonstrated high accuracy, as evidenced by calibration and ROC curve analyses. Immune infiltration studies revealed significant correlations between core targets and immune cell populations. Molecular docking confirmed that DEHP efficiently binds to core targets such as KRAS, BCL2, and IL6, supporting the hypothesis that it mediates brain injury via key signaling pathways. This study provides a comprehensive understanding of DEHP's neurotoxic mechanisms, offering valuable insights into its molecular basis and contributing to the future development of toxicological research and environmental risk assessment frameworks.