Abstract
This study investigated the molecular mechanisms by which phthalates induce depression, utilizing network toxicology and molecular docking techniques. By integrating the TargetNet, GeneCards, and PharmMapper databases, 658 potential target genes of phthalates were identified. Additionally, 5433 depression-related targets were retrieved from the GeneCards and OMIM databases. Comparative analysis revealed 360 common targets implicated in both phthalate action and depression. A Protein-Protein Interaction (PPI) network was constructed using the STRING database. Subsequently, the CytoHubba plugin (employing the MCC algorithm) within Cytoscape was used to screen the network, identifying the top 20 hub genes. These core genes include AKT1, CASP3, TNF, TP53, BCL2, and IL6, among others. Validation on the GEO dataset (GSE23848) revealed that the expression of multiple core genes was significantly upregulated in patients with depression (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that phthalates mainly regulate biological processes such as extracellular stimulus response, lipopolysaccharide metabolism, and chemical synaptic transmission. Depression is mediated by the AGE-RAGE signaling pathway (a complication of diabetes), lipids and atherosclerosis, Endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking confirmed that phthalates have strong binding activity with key targets (CASP3, TNF, TP53, BCL2, IL6). These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants.