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.

中文翻译：

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FDA 批准的双硫仑通过阻止 gasdermin D 孔的形成来抑制细胞焦亡。

骨髓和屏障上皮细胞对病原体和损伤的细胞溶质感应组装称为炎性体的大型复合物，其激活炎性半胱天冬酶以处理细胞因子 (IL-1β) 和 gasdermin D (GSDMD)。裂解的 GSDMD 形成膜孔，导致细胞因子释放和炎症细胞死亡（细胞焦亡）。抑制 GSDMD 是抑制炎症的一种有吸引力的策略。在这里，我们将双硫仑（一种用于治疗酒精成瘾的药物）鉴定为 GSDMD 的孔形成抑制剂，而不是 GSDM 家族的其他成员。双硫仑阻断细胞焦亡和细胞因子释放以及脂多糖诱导的小鼠脓毒性死亡。在纳摩尔浓度下，双硫仑共价修饰 GSDMD 中的人/小鼠 Cys191/Cys192 以阻止孔形成。双硫仑仍然允许 IL-1β 和 GSDMD 加工，但消除了孔形成，从而防止 IL-1β 释放和细胞焦亡。双硫仑在抑制 GSDMD 中的作用为重新利用这种安全药物来对抗炎症提供了新的治疗适应症，炎症导致许多人类疾病。