Targeting the NLRP3: From Novel Inhibitor Design to Clinic Trials and Therapeutic Applications

Dear Colleagues,

The NLRP3 inflammasome is a multiprotein complex that plays a critical role in mediating immune responses and maintaining homeostasis in the presence of pathogenic threats and danger signals. Dysregulated activation of NLRP3 has been implicated in a wide range of pathophysiological conditions, including metabolic disorders (diabetes, obesity, gout), cardiovascular diseases (atherosclerosis), neurological disorders (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis), and autoinflammatory syndromes (CAPS), as well as various cancers and chronic inflammatory diseases. These associations underscore its importance as a promising therapeutic target.

The activation of the NLRP3 inflammasome occurs through two sequential steps: priming and activation. Interference with this process can involve multiple molecular targets and events, including transcriptional regulation (e.g., via Toll-like receptor signaling), post-translational modifications (PTMs), and intracellular mechanisms such as K⁺ efflux, mitochondrial dysfunction, reactive oxygen species (ROS) production, and lysosomal disruption. In addition, targeting the disruption of inflammasome complex assembly, caspase-1 activation, and gasdermin D (GSDMD) cleavage represents an effective strategy for inhibiting NLRP3 inflammasome activation. In comparison, the direct inhibition of NLRP3 offers more precise control over the inflammatory cascade, potentially minimizing the off-target effects associated with less specific strategies. Consequently, the development of highly selective, direct NLRP3 inhibitors has emerged as a major focus in drug discovery.

This Special Issue will showcase papers highlighting the latest advances in the development of direct NLRP3 inhibitors, particularly those that have entered clinical trials, as well as their emerging therapeutic applications.

Dr. Yiming Xu
Dr. Yana Cen
Guest Editors

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