Diseases associated with chronic inflammation constitute a major health burden across the world. As central instigators of the inflammatory response to infection and tissue damage, inflammasomes — and the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome in particular — have emerged as key regulators in diverse rheumatic, metabolic and neurodegenerative diseases. Similarly to other inflammasome sensors, NLRP3 assembles a cytosolic innate immune complex that activates the cysteine protease caspase-1, which in turn cleaves gasdermin D (GSDMD) to induce pyroptosis, a regulated mode of lytic cell death. Pyroptosis is highly inflammatory, partly because of the concomitant extracellular release of the inflammasome-dependent cytokines IL-1β and IL-18 along with a myriad of additional danger signals and intracellular antigens. Here, we discuss how NLRP3 and downstream inflammasome effectors such as GSDMD, apoptosis-associated speck-like protein containing a CARD (ASC) and nerve injury-induced protein 1 (NINJ1) have gained significant traction as therapeutic targets. We highlight the recent progress in developing small-molecule and biologic inhibitors that are advancing into the clinic and serving to harness the broad therapeutic potential of modulating the NLRP3 inflammasome.

与慢性炎症相关的疾病构成了全世界的主要健康负担。作为对感染和组织损伤的炎症反应的核心刺激因素，炎性小体——尤其是 NACHT、LRR 和 PYD 结构域的蛋白 3 （NLRP3） 炎性小体——已成为各种风湿病、代谢病和神经退行性疾病的关键调节因子。与其他炎性小体传感器类似，NLRP3 组装一种胞质先天免疫复合物，该复合物激活半胱氨酸蛋白酶 caspase-1，进而裂解 gasdermin D （GSDMD） 以诱导焦亡，这是一种调节的裂解细胞死亡模式。细胞焦亡具有高度炎症性，部分原因是伴随着炎症小体依赖性细胞因子 IL-1β 和 IL-18 的细胞外释放，以及无数额外的危险信号和细胞内抗原。在这里，我们讨论了 NLRP3 和下游炎性小体效应子，如 GSDMD、含有 CARD （ASC） 的凋亡相关斑点样蛋白和神经损伤诱导蛋白 1 （NINJ1） 如何作为治疗靶点获得显着牵引力。我们重点介绍了开发小分子和生物抑制剂的最新进展，这些抑制剂正在进入临床，并有助于利用调节 NLRP3 炎性小体的广泛治疗潜力。