FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation

• Published in: Nature immunology Vol. 21; no. 7; pp. 736 - 745
• Main Authors: Hu, Jun Jacob, Liu, Xing, Xia, Shiyu, Zhang, Zhibin, Zhang, Ying, Zhao, Jingxia, Ruan, Jianbin, Luo, Xuemei, Lou, Xiwen, Bai, Yang, Wang, Junhong, Hollingsworth, L. Robert, Magupalli, Venkat Giri, Zhao, Li, Luo, Hongbo R., Kim, Justin, Lieberman, Judy, Wu, Hao
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2020; Nature Publishing Group
• Subjects: 631/250/256/1980; 631/250/256/2177; Addictions; Alcoholism; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology industry; Caspase 1 - genetics; Caspase 1 - metabolism; Caspase Inhibitors - pharmacology; Caspases - metabolism; Caspases, Initiator - genetics; Caspases, Initiator - metabolism; Cell death; Cell Line, Tumor; Cytokines; Disulfiram; Disulfiram - pharmacology; Disulfiram - therapeutic use; Drug abuse; Drug addiction; Drug approval; Drug Evaluation, Preclinical; Drug Repositioning; Epithelial cells; Female; HEK293 Cells; High-Throughput Screening Assays; Humans; IL-1β; Immunology; Infectious Diseases; Inflammasomes; Inflammation; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipopolysaccharides; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - immunology; Liposomes; Mice; Mitogens; Mutagenesis, Site-Directed; Phosphate-Binding Proteins - antagonists & inhibitors; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - metabolism; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - immunology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sepsis - drug therapy; Sepsis - immunology; Sf9 Cells; Spodoptera; United States; Massachusetts
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-0669-6

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.
Disulfiram is an FDA-approved drug for treating alcoholism. Wu and colleagues show that disulfiram can be repurposed to efficiently inhibit pyroptosis by specifically blocking gasdermin-mediated pore formation.