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

By J. Hu, Xing Liu, S. Xia, Zhibin Zhang, Ying Zhang, Jingxia Zhao, J. Ruan, Xuemei Luo, Xiwen Lou, Yang Bai and 8 more. Nature Immunology, 2020

977 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/2f4c77322d3f6175d6e2fbe55979fad0899844a5

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Citations in the corpus

• Role of pyroptosis in inflammation and cancer (2022, background): “Disulfiram is commonly used as an alcoholism drug approved by the FDA, but it was recently confirmed to modify Cys191 of GSDMD covalently to inhibit GSDMD-NT oligomerization, which is also applicable to the treatment of sepsis [277, 278].”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Recent research by Jun Jacob Hu and colleagues suggests that the use of disulfiram also prevents pyroptosis by preventing the creation of GSDMD pores in a mouse model of inflammation [326].”