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

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Inflammasomes sense pathogens and damage, activating caspases to process IL-1β and gasdermin D (GSDMD).
• Cleaved GSDMD forms pores, causing cytokine release and pyroptosis, a key inflammatory cell death pathway.
• Targeting GSDMD is a promising strategy to control inflammation.

Purpose of the Study:

• To identify inhibitors of GSDMD pore formation.
• To evaluate disulfiram, an alcohol addiction drug, as a potential GSDMD inhibitor.
• To explore therapeutic applications of disulfiram in inflammatory diseases.

Main Methods:

• Cell-based assays to assess pyroptosis and cytokine release.
• In vivo studies using a lipopolysaccharide-induced sepsis mouse model.
• Biochemical analysis to determine the mechanism of disulfiram inhibition on GSDMD.

Main Results:

• Disulfiram selectively inhibited GSDMD pore formation without affecting other GSDM family members.
• Disulfiram treatment prevented pyroptosis and IL-1β release in cellular models.
• Disulfiram administration reduced mortality in a mouse model of septic death.
• Disulfiram covalently bound to Cys191/Cys192 in GSDMD, abrogating pore formation at nanomolar concentrations.

Conclusions:

• Disulfiram effectively inhibits GSDMD-mediated pyroptosis and cytokine release.
• Disulfiram's ability to block GSDMD pore formation presents a novel therapeutic strategy for inflammatory conditions.
• Repurposing disulfiram offers a safe and accessible approach to combatting inflammation-related diseases.