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<p>Systemic lupus erythematosus (SLE) has a complex, multifactorial etiology, which contributes to a lack of definitive cure and limited treatment efficacy. Here, we report that cyclic GMP-AMP synthase (cGAS) is significantly activated in SLE patients. We further demonstrate that cGAS deletion protects mice from lupus-like symptoms induced by the TLR7 agonist imiquimod (IMQ). In a screen of 3,159 FDA-approved drugs, we identify the antiplatelet agent prasugrel as a potent cGAS inhibitor. Mechanistically, prasugrel disrupts the DNA-triggered liquid phase condensation and activation of cGAS via direct acetylation. Strikingly, we find that prasugrel exhibits remarkable efficacy in treating SLE in both mouse models and patient cells. Importantly, we report elevated plasma cyclic GMP-AMP (cGAMP) in SLE patients and identify it as a potential biomarker for predicting prasugrel response. Thus, our work elucidates the essential role of cGAS in SLE pathogenesis and presents prasugrel as a promising therapeutic option with immediate translational potential.</p>

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Prasugrel inhibits TLR7-driven autoimmunity in systemic lupus erythematosus by acetylating cGAS

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月18日

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  • Zeng-Lin Guo,
  • Li-Ming Sun,
  • Shuai Jiang,
  • Ming Zhao,
  • Yuhui Li,
  • Jinjing Qian,
  • Yakai Fu,
  • Chunmei Wu,
  • Ying Yuan,
  • Wen Xue,
  • Shao-Zhen Jiang,
  • Sen-Chao Yuan,
  • Xucheng Lv,
  • Xingxing Yang,
  • Lehua Yin,
  • Peng-Peng Zhu,
  • Yu Yu,
  • Xin Xu,
  • Kai Wang,
  • Qiu-Ying Han,
  • Zhuoxin Li,
  • Zhi-Hui Su,
  • Xi-Ping Yu,
  • Jiaqi Wu,
  • Hong Cai,
  • Tian Xia,
  • Yuan Chen,
  • Xue-Min Zhang,
  • Wei-Hua Li,
  • Ai-Ling Li,
  • Tao Zhou,
  • Zhanguo Li,
  • Qiong Fu,
  • Xinhua He,
  • Tao Li

摘要

Systemic lupus erythematosus (SLE) has a complex, multifactorial etiology, which contributes to a lack of definitive cure and limited treatment efficacy. Here, we report that cyclic GMP-AMP synthase (cGAS) is significantly activated in SLE patients. We further demonstrate that cGAS deletion protects mice from lupus-like symptoms induced by the TLR7 agonist imiquimod (IMQ). In a screen of 3,159 FDA-approved drugs, we identify the antiplatelet agent prasugrel as a potent cGAS inhibitor. Mechanistically, prasugrel disrupts the DNA-triggered liquid phase condensation and activation of cGAS via direct acetylation. Strikingly, we find that prasugrel exhibits remarkable efficacy in treating SLE in both mouse models and patient cells. Importantly, we report elevated plasma cyclic GMP-AMP (cGAMP) in SLE patients and identify it as a potential biomarker for predicting prasugrel response. Thus, our work elucidates the essential role of cGAS in SLE pathogenesis and presents prasugrel as a promising therapeutic option with immediate translational potential.