Spatial control of NLRP3 inflammasome assembly by membrane lipid composition

The NLRP3 inflammasome has been shown to assemble on multiple organelles, including the mitochondria, endoplasmic reticulum, trans-Golgi network, and endosomes. Yet, the precise site of assembly remains unresolved. Emerging evidence suggests that membrane lipid composition may play a critical role with phosphoinositides, cholesterol, and cardiolipin, alongside membrane biophysical properties and cellular metabolic state, collectively shaping membranes where inflammasome assembles. Here, we review how lipid-dependent mechanisms regulate NLRP3 assembly across membranes and consider whether a defined membrane lipid signature governs inflammasome assembly. This understanding may have broader implications for therapeutic targeting in inflammatory and metabolic diseases.