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

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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.

STP1, a structurally modified derivative of triptolide with improved safety, alleviates murine systemic lupus erythematosus by targeting and inhibiting Fyn, a Src kinase family member that regulates B- and T- cell responses.

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Fig. 1: Oral administration of STP1 ameliorates imiquimod-induced murine SLE.
Fig. 2: STP1 normalizes pathogenic B cell subsets in vivo.
Fig. 3: STP1 regulates BCR-mediated B cell activation and differentiation in vitro.
Fig. 4: STP1 alters cellular responses triggered by TLRs.
Fig. 5: STP1 alters Tfh cell differentiation in vitro.
Fig. 6: Identification of Fyn as a direct target of STP1.
Fig. 7

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82293684, 82204410, 22277144), the National Key R&D Program of China (2020YFA0908004), CAMS Innovation Fund for Medical Science of China (2022-I2M-1-028).

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  1. These authors contributed equally: Qiao-yi Ding, Yu Zhou, Hao-wen Luo

Authors and Affiliations

  1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    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

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  1. Qiao-yi Ding
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Contributions

QYD and YZ performed the experiments; QYD analyzed the data and wrote the paper; YZW contributed to the investigation; YFF and HWL performed data visualization; HWL, YDZ, and DMZ provided the compound; YZ and TTZ provided funding support; LW, CJC, and TTZ supervised the work and revised the paper.

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Correspondence to Cheng-juan Chen, Ying-da Zang or Tian-tai Zhang.

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Ding, Qy., Zhou, Y., Luo, Hw. et al. Triptolide derivative STP1 ameliorates murine systemic lupus erythematosus via targeting Fyn kinase. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01753-5

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