Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.

危险信号是许多常见炎性疾病的标志，这些刺激可以起到激活胞浆先天性免疫信号受体NLRP3（含NOD，LRR和吡啶3的功能）的作用。激活后，NLRP3使炎性小体的组装成核，从而导致白介素-1β（IL-1β）系列细胞因子的caspase 1介导的蛋白水解激活，并引起炎性，焦灼的细胞死亡。NLRP3活化的药理抑制作用可在多种炎性疾病的啮齿动物模型中产生有效的治疗作用，这种作用已通过NLRP3的基因消融反映出来。尽管这些发现凸显了NLRP3作为药物靶标的潜力，但对NLRP3结构和激活机制的了解还不完整，阻碍了针对该目标的新型疗法的发现和开发。在这里，我们回顾了我们对NLRP3激活和调控的了解的最新进展，重点介绍了NLRP3调节剂的发展前景，并讨论了用新型小分子药理靶向NLRP3的机会。