NLR inflammasome pathways: key targets for pathogenesis and therapy of metabolic diseases

The NOD-like receptor (NLR) inflammasome system is an evolutionarily conserved intracellular surveillance network that responds to pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and metabolism-associated molecular patterns (MAMPs). Beyond the well-characterized NLRP3 inflammasome, accumulating evidence suggests that NLRP1, NLRP6, NLRC5, NLRP12, and NLRP2 are also implicated in metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD). This review summarizes the molecular mechanisms governing NLR inflammasome activation and discusses the divergent, context-dependent roles of selected NLR family members in metabolic inflammation. We distinguish established inflammasome-dependent pathways from emerging inflammasome-independent and PANoptosis-related mechanisms, with particular attention to species differences, disease context, and strength of evidence. Therapeutic strategies targeting inflammasome components or downstream effectors are critically evaluated, including small-molecule inhibitors, cytokine blockade, peptide-derived agents, and natural bioactive compounds. By integrating mechanistic findings with a translational evidence hierarchy spanning in vitro studies, animal models, human observational data, early clinical trials, randomized evidence, and approved or repurposed anti-inflammatory therapies, this review highlights both the promise and limitations of precision inflammasome modulation for metabolic disease intervention, providing an evidence-graded therapeutic perspective on NLR biology in metabolic disease.