Zhang Ruiqiu, Wen Hairuo, Lin Zhi, Li Bo, Zhou Xiaobing, Wang Qingli
National Institutes for Food and Drug Control, Chinese Academy of Medical-Sciences and Peking Union Medical College, Beijing 100730, China.
National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing 100176, China.
Int J Mol Sci. 2025 Aug 24;26(17):8215. doi: 10.3390/ijms26178215.
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 ( < 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.
本研究利用网络毒理学和分子对接技术，探究了邻苯二甲酸酯诱导抑郁症的分子机制。通过整合TargetNet、GeneCards和PharmMapper数据库，确定了658个邻苯二甲酸酯的潜在靶基因。此外，从GeneCards和OMIM数据库中检索到5433个与抑郁症相关的靶点。比较分析揭示了360个在邻苯二甲酸酯作用和抑郁症中均涉及的共同靶点。使用STRING数据库构建了蛋白质-蛋白质相互作用（PPI）网络。随后，利用Cytoscape中的CytoHubba插件（采用MCC算法）对网络进行筛选，确定了前20个枢纽基因。这些核心基因包括AKT1、CASP3、TNF、TP53、BCL2和IL6等。对GEO数据集（GSE23848）的验证表明，抑郁症患者中多个核心基因的表达显著上调（<0.05）。基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析表明，邻苯二甲酸酯主要调节细胞外刺激反应、脂多糖代谢和化学突触传递等生物过程。抑郁症由AGE-RAGE信号通路（糖尿病并发症）、脂质与动脉粥样硬化、内分泌抵抗以及PI3K-Akt信号通路介导。分子对接证实邻苯二甲酸酯与关键靶点（CASP3、TNF、TP53、BCL2、IL6）具有很强的结合活性。这些发现为评估环境污染物带来的健康风险提供了一种新的模式。
