Prasugrel inhibits TLR7-driven autoimmunity in systemic lupus erythematosus by acetylating cGAS
Abstract
Abstract 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.
Article Details
Authors (35)
Zeng-Lin Guo
Li-Ming Sun
Shuai Jiang
State Key Laboratory of Chemical Reaction Dynamics and Dalian Coherent Light Source, Dalian Institute of Chemical Physics
Ming Zhao
Yuhui Li
Department of Rheumatology and Immunology, Peking University People’s Hospital
Jinjing Qian
Yakai Fu
Chunmei Wu
Ying Yuan
Wen Xue
Shao-Zhen Jiang
Sen-Chao Yuan
Xucheng Lv
Xingxing Yang
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering
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
School of Chemical and Biomolecular Engineering
Xue-Min Zhang
Wei-Hua Li
Ai-Ling Li
Tao Zhou
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Zhanguo Li
Qiong Fu
Xinhua He
Institute of Eco-environment and Industrial Technology, Shanxi Agricultural University
Tao Li