Sensing the spectrum: diverse stimuli for the NLRP3 inflammasome

The NLRP3 inflammasome is a central inflammatory signaling pathway in host defense, cancer, metabolic disorders, and neurodegenerative diseases. Unlike other pattern-recognition receptors, NLRP3 senses perturbations in organelle integrity and ion homeostasis, enabling its activation by a remarkably broad spectrum of pathogen-derived and cellular stress signals. In this review, we summarize recent advances that have expanded our understanding of the diverse classes of NLRP3 stimuli and highlight breakthroughs in elucidating the molecular mechanisms underlying both infection-driven and sterile inflammation. Finally, we discuss unresolved questions surrounding the physiological relevance of NLRP3 stimuli and the nature of uncharacterized stimuli in sterile inflammatory diseases, emphasizing how resolving these gaps may inform targeted therapeutic development.