Lipid-NLRP3 interplay in inflammasome regulation

NLRP3 is a cytosolic innate immune sensor that detects PAMPs and DAMPs and, together with ASC, activates caspase-1 to drive IL-1β/IL-18 release and pyroptotic cell death. A major open question is how such diverse triggers funnel into a single molecular switch within NLRP3. Emerging evidence points to lipids as central integrators: they act as direct NLRP3 ligands, post-translational modifiers, and membrane scaffolds that choreograph inflammasome priming and assembly. Palmitoylation dynamically tunes NLRP3 stability, localization, and activation thresholds, while cardiolipin and PI4P function as organelle-specific lipid cues that recruit and activate NLRP3 at mitochondria and Golgi/endosomal membranes. NLRP3 also senses shifts in cholesterol, fatty acids, and ceramides, mechanistically linking lipid imbalance to cardiometabolic and inflammatory disease. In this review, we spotlight how specific lipid-NLRP3 interactions and lipid-driven post-translational modifications orchestrate inflammasome priming and activation across cellular membranes.