2. Academic Validation
  3. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity

CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity

  • Signal Transduct Target Ther. 2022 Jun 24;7(1):190. doi: 10.1038/s41392-022-01018-7.
Liliang Li  # 1 2,  Pan Gao  # 3,  Xinru Tang 4,  Zheng Liu 4,  Mengying Cao 3,  Ruoyu Luo 5,  Xiaoqing Li 4,  Jing Wang 4,  Xinyi Lin 4,  Chao Peng 6,  Zhihong Li 6,  Jianhua Zhang 7,  Xian Zhang 8,  Zhonglian Cao 9,  Yunzeng Zou 10,  Li Jin 11 12
Affiliations

Affiliations

  • 1 Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 2 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China. [email protected].
  • 3 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 4 Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 5 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
  • 6 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China.
  • 7 Academy of Forensic Science, Ministry of Justice, and Shanghai Key Laboratory of Forensic Medicine, Shanghai, 200063, China.
  • 8 Department of Cardiology, Kunshan Hospital of Integrated Traditional Chinese and Western Medicine, Kunshan, Jiangsu, 215301, China.
  • 9 School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 10 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 11 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China. [email protected].
  • 12 Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 35739093 DOI: 10.1038/s41392-022-01018-7
Abstract

Long-term use of antipsychotics is a common cause of myocardial injury and even sudden cardiac deaths that often lead to drug withdrawn or discontinuation. Mechanisms underlying antipsychotics cardiotoxicity remain largely unknown. Herein we performed RNA sequencing and found that NLRP3 inflammasome-mediated Pyroptosis contributed predominantly to multiple antipsychotics cardiotoxicity. Pyroptosis-based small-molecule compound screen identified Cannabinoid Receptor 1 (CB1R) as an upstream regulator of the NLRP3 inflammasome. Mechanistically, antipsychotics competitively bond to the CB1R and led to CB1R translocation to the cytoplasm, where CB1R directly interacted with NLRP3 inflammasome via amino acid residues 177-209, rendering stabilization of the inflammasome. Knockout of Cb1r significantly alleviated antipsychotic-induced cardiomyocyte Pyroptosis and cardiotoxicity. Multi-organ-based investigation revealed no additional toxicity of newer CB1R antagonists. In authentic human cases, the expression of CB1R and NLRP3 inflammasome positively correlated with antipsychotics-induced cardiotoxicity. These results suggest that CB1R is a potent regulator of the NLRP3 inflammsome-mediated Pyroptosis and small-molecule inhibitors targeting the CB1R/NLRP3 signaling represent attractive approaches to rescue cardiac side effects of antipsychotics.

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