Zhang Lun, Huang Qianqian, Yu Yun, Jiang Yue, Hou Mengzhen, Tao Wenkang, Zhang Cheng, Wang Jianqing
Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230012, China.
Anhui Public Health Clinical Center, Hefei, 230012, China.
Sci Rep. 2025 Jul 1;15(1):22031. doi: 10.1038/s41598-025-05489-w.
The objective of this study was to investigate the hepatotoxic effects and molecular mechanisms underlying di(2-ethylhexyl) phthalate (DEHP)-induced intrahepatic cholestasis of pregnancy (ICP) through a network toxicology approach. Utilizing liver transcriptomics in conjunction with the GeneCards, DisGeNET, and OMIM databases, we identified 151 potential targets associated with DEHP-induced ICP. Subsequent analyses employing STRING and cytoscape software revealed five core targets: EGFR, STAT3, JUN, FOS, and HSP90AA1. Functional enrichment analysis via gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways indicated significant involvement in cholesterol synthesis, bile salt secretion, and the MAPK signaling pathway. Molecular docking studies conducted using AutoDock demonstrated strong binding affinities between DEHP and these core targets. In conclusion, this study offers novel insights into the molecular mechanisms of DEHP-induced hepatotoxicity during pregnancy while providing a systematic framework for assessing risks associated with DEHP exposure; thus contributing to the prevention and treatment of ICP.
本研究的目的是通过网络毒理学方法，研究邻苯二甲酸二（2-乙基己基）酯（DEHP）诱导的妊娠期肝内胆汁淤积症（ICP）的肝毒性作用及其分子机制。利用肝脏转录组学结合GeneCards、DisGeNET和OMIM数据库，我们鉴定了151个与DEHP诱导的ICP相关的潜在靶点。随后使用STRING和Cytoscape软件进行的分析揭示了五个核心靶点：表皮生长因子受体（EGFR）、信号转导和转录激活因子3（STAT3）、原癌基因蛋白Jun（JUN）、原癌基因蛋白Fos（FOS）和热休克蛋白90α家族成员1（HSP90AA1）。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路进行的功能富集分析表明，这些靶点显著参与胆固醇合成、胆盐分泌和丝裂原活化蛋白激酶（MAPK）信号通路。使用AutoDock进行的分子对接研究表明，DEHP与这些核心靶点之间具有很强的结合亲和力。总之，本研究为妊娠期DEHP诱导的肝毒性分子机制提供了新的见解，同时为评估DEHP暴露相关风险提供了一个系统框架；从而有助于ICP的预防和治疗。
