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<p>Tripterygium wilfordii Hook.f. (TW) is widely used in the treatment of rheumatoid arthritis (RA) but is associated with significant safety concerns. This study aimed to characterize the immune-centered toxicity profile of TW using an integrative network toxicology approach. Bioactive compounds of TW were collected from phytochemical databases. In silico toxicity prediction, target fishing, protein–protein interaction (PPI) network construction, Gene Ontology (GO) and KEGG pathway enrichment, and molecular docking were integrated to systematically evaluate potential toxicological mechanisms, with a particular focus on immunotoxicity. In silico toxicity profiling revealed a dominant immunotoxicity signal (probability 0.97), while classical organ toxicities (hepatotoxicity, nephrotoxicity, cardiotoxicity, and neurotoxicity) were predicted to be inactive. Network analysis identified key immune-related hub genes, including TNF, IL6, STAT3, MAPK1, and JUN. Pathway enrichment analysis highlighted TNF signaling, NF-κB signaling, JAK-STAT signaling, and Th17 cell differentiation as critical convergent pathways linking therapeutic effects and immune-related adverse outcomes. Molecular docking further confirmed stable binding affinities between major TW bioactive compounds and these core immune targets. This study demonstrates that the toxicity profile of TW is predominantly driven by immune dysregulation rather than direct organ injury. The network toxicology framework provides a systems-level understanding of TW-induced immunotoxicity and offers valuable mechanistic insights for safer clinical application and risk mitigation of multi-component herbal immunomodulators.</p>

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Immune-centered toxicity profiling of Tripterygium wilfordii in rheumatoid arthritis using network toxicology and predictive modeling

  • 期刊论文

  • 发表日期：

    2026年6月1日

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  • Haiyang Kou,
  • Huaiquan Liu,
  • Lingyan Lai,
  • Shili Yang,
  • Xinyan Zhang,
  • Yu Sun,
  • Yunling Xu,
  • Bo Chen

摘要

Tripterygium wilfordii Hook.f. (TW) is widely used in the treatment of rheumatoid arthritis (RA) but is associated with significant safety concerns. This study aimed to characterize the immune-centered toxicity profile of TW using an integrative network toxicology approach. Bioactive compounds of TW were collected from phytochemical databases. In silico toxicity prediction, target fishing, protein–protein interaction (PPI) network construction, Gene Ontology (GO) and KEGG pathway enrichment, and molecular docking were integrated to systematically evaluate potential toxicological mechanisms, with a particular focus on immunotoxicity. In silico toxicity profiling revealed a dominant immunotoxicity signal (probability 0.97), while classical organ toxicities (hepatotoxicity, nephrotoxicity, cardiotoxicity, and neurotoxicity) were predicted to be inactive. Network analysis identified key immune-related hub genes, including TNF, IL6, STAT3, MAPK1, and JUN. Pathway enrichment analysis highlighted TNF signaling, NF-κB signaling, JAK-STAT signaling, and Th17 cell differentiation as critical convergent pathways linking therapeutic effects and immune-related adverse outcomes. Molecular docking further confirmed stable binding affinities between major TW bioactive compounds and these core immune targets. This study demonstrates that the toxicity profile of TW is predominantly driven by immune dysregulation rather than direct organ injury. The network toxicology framework provides a systems-level understanding of TW-induced immunotoxicity and offers valuable mechanistic insights for safer clinical application and risk mitigation of multi-component herbal immunomodulators.