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<p>Triptolide has demonstrated potent immunosuppressive properties in multiple autoimmune disorders, but its severe toxicity has greatly hampered clinical application. Here, we synthesized a triptolide derivative STP1, which exhibits remarkably reduced toxicity compared with triptolide. Immune dysfunction plays a critical role in systemic lupus erythematosus (SLE), an archetypical and refractory autoimmune disorder with limited therapeutic options and suboptimal outcomes. To elucidate the drugability and effect, we investigated the therapeutic potential, safety, regulatory mechanism and target of STP1 on SLE. Our data indicated that STP1 significantly ameliorates imiquimod-induced murine SLE by reducing anti-IgG, anti-dsDNA IgG, proteinuria, and renal pathological injury. Mechanistically, STP1 exerts markedly immunosuppressive roles by modulating the differentiation of B cell into plasma cells and T cell into Tfh cells. Further investigation showed that STP1 regulates B-cell receptor and T-cell receptor signaling by directly targeting Fyn kinase responsible for its immunosuppressive activity. For safety of STP1, our findings indicated that the STP1 did not show any toxicity in biochemical parameters and organ pathological analysis in subacute toxicity experiment. The findings suggested that STP1 is an attractive novel candidate for SLE and other autoimmune diseases for thorough evaluation.</p><p></p>

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Triptolide derivative STP1 ameliorates murine systemic lupus erythematosus via targeting Fyn kinase

  • 期刊论文

  • 发表日期：

    2026年2月11日

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  • Qiao-yi Ding,
  • Yu Zhou,
  • Hao-wen Luo,
  • Ya-zi Wei,
  • Yi-fan Feng,
  • Dong-ming Zhang,
  • Lei Wu,
  • Cheng-juan Chen,
  • Ying-da Zang,
  • Tian-tai Zhang

摘要

Triptolide has demonstrated potent immunosuppressive properties in multiple autoimmune disorders, but its severe toxicity has greatly hampered clinical application. Here, we synthesized a triptolide derivative STP1, which exhibits remarkably reduced toxicity compared with triptolide. Immune dysfunction plays a critical role in systemic lupus erythematosus (SLE), an archetypical and refractory autoimmune disorder with limited therapeutic options and suboptimal outcomes. To elucidate the drugability and effect, we investigated the therapeutic potential, safety, regulatory mechanism and target of STP1 on SLE. Our data indicated that STP1 significantly ameliorates imiquimod-induced murine SLE by reducing anti-IgG, anti-dsDNA IgG, proteinuria, and renal pathological injury. Mechanistically, STP1 exerts markedly immunosuppressive roles by modulating the differentiation of B cell into plasma cells and T cell into Tfh cells. Further investigation showed that STP1 regulates B-cell receptor and T-cell receptor signaling by directly targeting Fyn kinase responsible for its immunosuppressive activity. For safety of STP1, our findings indicated that the STP1 did not show any toxicity in biochemical parameters and organ pathological analysis in subacute toxicity experiment. The findings suggested that STP1 is an attractive novel candidate for SLE and other autoimmune diseases for thorough evaluation.