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.