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<p>Plasticizers, such as dimethyl phthalate (DMP), diethyl phthalate (DEP), and dioctyl phthalate (DOP), are ubiquitously used in industrial products but pose potential hepatotoxic risks. This study employs network toxicology, molecular docking, and molecular dynamics (MD) simulations to investigate the molecular mechanisms underlying plasticizer-induced liver damage. The potential targets of DMP, DEP, and DOP were predicted using multiple databases (ChEMBL, STITCH, etc.), and liver damage-related genes were retrieved from GeneCards, OMIM, and DisGeNET. Overlapping targets were identified through Venn diagrams. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, with hub genes prioritized by the Maximal Clique Centrality(MCC) algorithm. Functional enrichment analysis (GO/KEGG) was performed to identify and characterize key pathways. Molecular docking (AutoDock Vina) and MD simulations (AMBER18) were used to validate interactions between plasticizers and key targets. A total of 100 overlapping targets were identified, with KRAS, KIT, LCK, NR3C1, and FLT1 emerging as hub genes. Enrichment analysis highlighted pathways including PI3K-Akt, Ras signaling, and proteoglycans in cancer. Molecular docking revealed stable interactions between FLT1-DEP/DMP and KIT-DOP, supported by MD simulations showing low RMSD/RMSF values. This integrative approach identifies critical targets (e.g., FLT1, KIT) and pathways (e.g., PI3K-Akt/Ras) that mediate plasticizer hepatotoxicity, providing novel insights into mechanistic pathways and potential therapeutic targets.</p>

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Exploring the mechanism of plasticizers action in liver damage based on network toxicology, molecular docking, and molecular dynamic simulation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月27日

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  • Cheng Feng,
  • Luo Chun,
  • Shang KeLei,
  • Tan XiaoGuang,
  • Wang HouHong,
  • Chen YongYun,
  • Xu MengLei,
  • Li Bin

摘要

Plasticizers, such as dimethyl phthalate (DMP), diethyl phthalate (DEP), and dioctyl phthalate (DOP), are ubiquitously used in industrial products but pose potential hepatotoxic risks. This study employs network toxicology, molecular docking, and molecular dynamics (MD) simulations to investigate the molecular mechanisms underlying plasticizer-induced liver damage. The potential targets of DMP, DEP, and DOP were predicted using multiple databases (ChEMBL, STITCH, etc.), and liver damage-related genes were retrieved from GeneCards, OMIM, and DisGeNET. Overlapping targets were identified through Venn diagrams. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, with hub genes prioritized by the Maximal Clique Centrality(MCC) algorithm. Functional enrichment analysis (GO/KEGG) was performed to identify and characterize key pathways. Molecular docking (AutoDock Vina) and MD simulations (AMBER18) were used to validate interactions between plasticizers and key targets. A total of 100 overlapping targets were identified, with KRAS, KIT, LCK, NR3C1, and FLT1 emerging as hub genes. Enrichment analysis highlighted pathways including PI3K-Akt, Ras signaling, and proteoglycans in cancer. Molecular docking revealed stable interactions between FLT1-DEP/DMP and KIT-DOP, supported by MD simulations showing low RMSD/RMSF values. This integrative approach identifies critical targets (e.g., FLT1, KIT) and pathways (e.g., PI3K-Akt/Ras) that mediate plasticizer hepatotoxicity, providing novel insights into mechanistic pathways and potential therapeutic targets.