NLRP3 Inflammasome Inhibitors as Precision Anti-inflammatory Pharmacotherapy: Translational Advances, Clinical Evidence, and Disease-specific Challenges.

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is pivotal ininnate immunity and inflammatory disease pathogenesis, notably through interleukins (IL)-1β and IL-18 and by triggering gasdermin D (GSDMD)-mediated pyroptosis. It has been implicated in cardiometabolic, renal, neuroinflammatory, and immune-mediated diseases, making NLRP3 a potential target for selective anti-inflammatory therapy. Clinical efficacy may vary according to disease biology, degree of NLRP3 inhibition, tissue distribution, and patient selection. This review covers the pharmacological and translational research of development of NLRP3 inhibitors and it summarizes the emerging clinical evidences from databases like PubMed, Scopus, Web of Science, Embase and ClinicalTrials.gov. It discusses several direct small-molecule NLRP3 inhibitors, including dapansutrile and selnoflastand others, including upstream activation mechanisms and downstream inflammatory mediators. Pharmacologic selectivity, potency, tissue distribution, activation of NLRP3 and clinical efficacy are among the key factors to consider in anti-inflammatory drug development. The success of these drugs in current use is variable, depending on the inflammatory type of the disease and the first generation of these drugs has shown liver toxicity. The role of the inflammasome in these conditions further supports the need for targeting NLRP3, especially in diseases such as cardiometabolic, renal and neuroinflammatory, but there are still hurdles to overcome, such as patient stratification and validation of biomarkers. Biomarker enriched populations should be targeted as a next step to improve the effectiveness of selective NLRP3 inhibition over current therapies.