The NLRP3 Inflammasome Across the AKI-AKD-CKD Continuum: Mitochondrial, Epigenetic and Endocrine-Metabolic Regulation

The NLRP3 inflammasome has emerged as a potential molecular link between cellular stress, sterile inflammation, and progressive kidney damage. This review critically examines canonical, non-canonical, and mitochondrial mechanisms of NLRP3 regulation across the acute kidney injury (AKI)-acute kidney disease (AKD)-chronic kidney disease (CKD) continuum, integrating their relationships with pyroptosis, maladaptive repair, fibrosis, and epigenetic regulation. Particular attention is given to endocrine-metabolic signals that may shape renal inflammasome activity. Hyperglycemia, advanced glycation end products, mitochondrial reactive oxygen species, TXNIP signaling, lipotoxicity, impaired tubular fatty-acid oxidation, podocyte insulin resistance, obesity-related adipokine imbalance, and aldosterone-mineralocorticoid receptor activation may converge on NLRP3. Conversely, inflammasome-dependent cytokine release and pyroptosis may amplify insulin resistance, metabolic dysfunction, and cardiorenal injury, establishing a bidirectional endocrine-renal inflammatory loop. Importantly, increased NLRP3 mRNA or protein abundance is distinguished from functional inflammasome activation, which is more strongly supported by downstream evidence such as ASC recruitment/oligomerization, caspase-1 activation, mature IL-1β/IL-18 production, GSDMD cleavage, or pyroptotic cell death. A central issue is whether NLRP3 is a causal driver of kidney disease or a marker of ongoing tissue injury. Although genetic and pharmacological studies support a pathogenic role in experimental models, clinical evidence remains largely associative and disease-dependent. NLRP3-related signals should therefore be regarded as candidate, rather than validated, biomarkers. SGLT2 inhibitors, GLP-1 receptor agonists and finerenone may indirectly attenuate NLRP3 signaling, but mechanistic mediation of their clinical benefits remains unproven. Defining cell-specific activation and clinical target engagement will be essential to establish NLRP3 as a biomarker and therapeutic target.