Sepsis remains one of the most common and lethal conditions globally. Currently, no proposed target specific to sepsis improves survival in clinical trials. Thus, an in-depth understanding of the pathogenesis of sepsis is needed to propel the discovery of effective treatment. Recently attention to sepsis has intensified because of a growing recognition of a non-canonical inflammasome-triggered lytic mode of cell death termed pyroptosis upon sensing cytosolic lipopolysaccharide (LPS). Although the consequences of activation of the canonical and non-canonical inflammasome are similar, the non-canonical inflammasome formation requires caspase-4/5/11, which enzymatically cleave the pore-forming protein gasdermin D (GSDMD) and thereby cause pyroptosis. The non-canonical inflammasome assembly triggers such inflammatory cell death by itself; or leverages a secondary activation of the canonical NLRP3 inflammasome pathway. Excessive cell death induced by oligomerization of GSDMD and NINJ1 leads to cytokine release and massive tissue damage, facilitating devastating consequences and death. This review summarized the updated mechanisms that initiate and regulate non-canonical inflammasome activation and pyroptosis and highlighted various endogenous or synthetic molecules as potential therapeutic targets for treating sepsis.

中文翻译：

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非典型炎症小体诱导的细胞焦亡和感染性休克。

脓毒症仍然是全球最常见和最致命的疾病之一。目前，临床试验中还没有提出针对脓毒症的特定目标可以提高生存率。因此，需要深入了解脓毒症的发病机制，以推动有效治疗的发现。最近，人们越来越多地认识到一种非典型的炎症小体触发的细胞死亡溶解模式，称为细胞焦亡，这种模式是在感测胞质脂多糖（LPS）时引起的。尽管经典和非经典炎症小体激活的后果相似，但非经典炎症小体的形成需要 caspase-4/5/11，它会酶切成孔蛋白gasdermin D (GSDMD)，从而导致细胞焦亡。非典型炎症小体组装会自行引发炎症细胞死亡。或利用经典 NLRP3 炎性体途径的二次激活。GSDMD 和 NINJ1 寡聚化诱导的过度细胞死亡会导致细胞因子释放和大规模组织损伤，从而导致毁灭性后果和死亡。这篇综述总结了启动和调节非典型炎症小体激活和细胞焦亡的最新机制，并强调了各种内源性或合成分子作为治疗脓毒症的潜在治疗靶点。