在炎症期间，炎症性胱天蛋白酶-1（CASP1）可以响应于传感病原体衍生的颗粒或宿主衍生的危险信号而在规范炎性激活的下游被激活（在Kelley N等人的审查中进行审查;郑D等人。2020）。在感测细胞内细菌脂多糖（LPS）（ViganoE等人2015）中，在小鼠中，通过Casp4，Casp1，在小鼠中的Casp4，Casp11中的患者介导的非典令的炎症组件（viganoe等。2015）。活化的炎症性血糖诱导促进促炎细胞死亡，通过燃气蛋白D（GSDMD）的蛋白水解加工（Shi J等人，2015; Kayagaki N等人。2015;他W等人2015; Ding J等，2016;刘X等。2016; SBORGI L等人。2016年EMBO J）。由于其C末端结构域的抑制功能，完整的GSDMD不能形成孔隙。Caspase介导的GSDMD的裂解释放GSDMD（276-484）的C末端片段（Shi J等，2015），使GSDMD（1-275）的N-末端片段形成为形成细胞因子的细胞膜中的毛孔释放和糊酶（Ding J等人。2016; Liu X等人。2016; Sborgi L等人2016; Mulvihill e等人2018）。白硫氨酸，也称为抗反应性药物，被发现抑制Nigericin诱导的NIGRICIN诱导的NLRP3介导的糊酶和LPS-灌注的人单核细胞单核细胞THP-1细胞中的炎性细胞因子释放（HU JJ等人2020）。通过LPS电穿孔在小鼠中的非规范（Caspase-11依赖性）小鼠炎症途径中获得了类似的结果。骨髓衍生的巨噬细胞（IBMDMS）（HU JJ等2020）。纳米液相色谱 - 串联质谱（Nano-LC-MS / MS）鉴定了人GSDMD中Cys191的二硫代乙基氨基甲酰基加合物，表明DISULVIRAM共价修饰的GSDMD CYS191。 The importance of Cys191 of GSDMD for disulfiram activity was further confirmed by a site‑directed mutational analysis (Hu JJ et al. 2020). In line with these findings, necrosulfonamide (NSA) was identified as a potent inhibitor of pyroptosis by targeting GSDMD at Cys191 (Rathkey JK et al. 2018), and dimethyl fumarate modifies Cys191 to form S-(2-succinyl)-cysteine and block pyroptosis (Humphries F et al. 2020). Cys191 in human GSDMD (corresponding to Cys192 in mouse) is thought to be critical for the GSDMD oligomerization and pore formation (reviewed in Pandeya A et al. 2019). Further, disulfiram allowed cleavage of pro‑interleukin 1β (IL‑1β) and GSDMD, but abrogated GSDMD pore formation and blocked IL‑1β release in human and mouse cells (Hu JJ et al. 2020). Moreover, GSDMD‑mediated pyroptosis when overactivated can lead to sepsis. Elevated levels of GSDMD were noted in microparticles isolated from plasma of septic patients (Homsy E et al. 2019). In the murine sepsis model, GSDMD‑deficient mice showed significantly improved survival compared to the wild type mice (Kambara H et al. 2018). Disulfiram activity protected mice from LPS‑induced septic shock (Hu JJ et al. 2020). The data suggest that disulfiram blocks GSDMD pore formation and pyroptosis by modifying Cys191 of GSDMD and point to the possibility of using disulfiram to counteract human diseases due to excessive inflammation (Hu JJ et al. 2020).
