Disulfiram suppresses NLRP3 inflammasome activation to treat peritoneal and gouty inflammation.

Free Radical Biology & Medicine
Wenmin DengPing Sun

Abstract

The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a vital role in mediating the innate immune system. Its aberrant activation contributes to the progression of several devastating diseases such as acute peritonitis, acute liver injury, sepsis, gout, and others. However, the medications targeting NLRP3 inflammasome are not available in the clinic. Reusing marketed drugs, which have been already proved to possess good pharmacokinetic profiles and safety, is a strategy to develop new NLRP3 inflammasome inhibitors for clinical trials. In this study, we identified disulfiram (DSF), an old marketed drug as a treatment for alcoholism, could effectively inhibit NLRP3 inflammasome activation and suppress pyroptotic cell death. DSF prevented lysosomal cathepsin B releasing into the cytoplasm, which in turn inactivated the NLRP3 inflammasome. DSF also reduced mitochondrial-independent ROS production. More importantly, treatment with DSF showed remarkable therapeutic effects on the LPS-induced peritoneal inflammation and MSU-induced gouty inflammation. This study provides a potential pharmacological approach to treating NLRP3-driven diseases and a tool to study NLRP3 biology.

Citations

Oct 9, 2020·Journal of Cellular and Molecular Medicine·Xin WangQingjiang Jin
Dec 24, 2020·Acta Biochimica Et Biophysica Sinica·Chenguang LiDongyun Ouyang
Apr 13, 2021·European Journal of Medicinal Chemistry·Cheng ZhangZhongjin Yang
Jul 30, 2021·Clinical and Translational Allergy·Hanna BonnekohKaroline Krause
Jul 30, 2021·Cellular & Molecular Immunology·Yi HuangRongbin Zhou
Sep 1, 2021·Journal of Neuroinflammation·Pengfei XuWei Hu
Sep 26, 2021·Acta Pharmacologica Sinica·An-Te OuYong-Zhuo Huang

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