Study on the Mechanism of DNHP's Effects on Brain Damage Based on Network Toxicology

Background Di-n-hexyl phthalate (DNHP) is a commonly used plasticizer, primarily employed in the manufacturing of rubber products, cosmetics, and several other industrial applications. Despite its extensive usage, research indicates that DNHP exhibits significant toxicity to the human body, particularly with long-term exposure. It has been shown to impair adipose tissue function, affect reproductive development, and cause damage to various organs via airborne particulate matter. However, the mechanisms through which DNHP induces brain injury (BI) remain poorly understood. Therefore, it is essential to conduct a risk assessment and mechanism exploration of DNHP-induced brain injury by integrating network toxicology approaches with molecular docking techniques. Methods This study employs network toxicology and molecular docking techniques to systematically assess the potential impact of Di-n-hexyl phthalate (DNHP) on brain injury. First, chemical information on DNHP is obtained from multiple databases (e.g., PubChem, ChEMBL, STITCH) to predict its target proteins and screen related genes. Then, brain injury-related target genes are extracted from databases such as GeneCard, OMIM, and TTD, and a “compound-target-disease” network is constructed by combining DNHP’s target genes. Protein-protein interaction analysis is performed to identify key targets involved in DNHP-induced brain injury, followed by Gene Ontology (GO) enrichment analysis and KEGG pathway analysis to reveal the underlying molecular mechanisms. Finally, molecular docking techniques are employed to validate the binding affinity between DNHP and its target proteins, providing further biological evidence. Results Di-n-hexyl phthalate (DNHP) exhibits significant nephrotoxicity, carcinogenicity, and blood-brain barrier toxicity. Through multi-database analysis, 448 DNHP target proteins and 2,810 brain injury-related targets were identified. From these, 130 overlapping targets were selected, and a “compound-target-disease”network was constructed. Protein-protein interaction network analysis identified three core targets—KRAS, HRAS, and NRAS—that play pivotal roles in DNHP-induced brain injury. Gene Ontology (GO) enrichment and KEGG pathway analyses revealed that DNHP-induced brain injury involves synaptic transmission, glutamatergic signaling, and several neuro-related pathways. Molecular docking analysis further suggested that DNHP may induce brain injury through its interaction with key targets such as KRAS, HRAS, and NRAS. Conclusion In summary, this study, through the use of network toxicology and molecular docking techniques, provides a comprehensive investigation into the mechanisms of DNHP-induced brain injury, offering both theoretical foundations and experimental support for the toxicity assessment of DNHP and strategies for brain injury prevention and treatment.