Deciphering the NEK7-NLRP3 inflammasome assembly: from conformational activation to allosteric drug discovery

The NLRP3 inflammasome, a pivotal component of innate immunity, orchestrates immune defense and inflammatory responses. NEK7, an essential upstream regulator, drives inflammasome assembly through direct interaction with NLRP3. This review systematically summarizes the molecular mechanisms, upstream regulatory networks, and therapeutic targeting of the NEK7-NLRP3 axis. Structurally, NEK7 binds to the leucine-rich repeat (LRR) domain of NLRP3 via its catalytic domain, inducing conformational rearrangement and oligomerization. This structural shift exposes NLRP3's PYRIN domain (PYD), enabling ASC recruitment through homotypic PYD-PYD interactions and subsequent pro-caspase-1 activation to form the mature inflammasome complex. At the regulatory level, cell cycle-dependent NEK7 availability, post-translational modifications (phosphorylation/ubiquitination/palmitoylation), and numerous upstream signals-including kinases, ubiquitin ligases, ionic fluxes, miRNAs, and pathogens-collectively fine-tune the NEK7-NLRP3 interaction. In terms of therapeutic targeting, natural compounds from traditional Chinese medicine (e.g., oridonin, pristimerin), synthetic inhibitors (e.g., MCC950, entrectinib), and biological agents have been shown to suppress inflammasome activation by disrupting the NEK7-NLRP3 interface or modulating associated regulatory pathways. These advances offer novel therapeutic strategies for NLRP3-driven pathologies including gouty arthritis, ischemia-reperfusion injury, neurodegenerative disorders, and metabolic syndromes.