Inflammasome-Driven Cardiac Fibrosis in Cardiometabolic Disease and Arrhythmias: Mechanisms, Biomarkers, and Therapeutic Targets.

Chronic low-grade inflammation and maladaptive extracellular matrix remodeling co-evolve across atrial fibrillation, heart failure phenotypes, diabetic cardiomyopathy, and aortic valve stenosis. Emerging data implicate inflammasome signaling-particularly NOD-like receptor pyrin domain-containing protein 3 (NLRP3), caspase-1 activation, interleukin (IL)-1β/IL-18 maturation, and gasdermin-mediated pyroptosis-as a proximal driver of profibrotic programs. This narrative review synthesizes mechanistic and translational evidence linking pyroinflammation to myofibroblast transition, transforming growth factor β (TGF-β)/small mother against decapentaplegic (SMAD) and Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) activation, matrix deposition and cross-linking, and resultant electrical and mechanical heterogeneity. We emphasize multicellular crosstalk among immune cells, fibroblasts, cardiomyocytes, endothelium/pericytes, and epicardial adipose tissue, and outline organ-axis amplification from kidney and liver disease. We appraise candidate biomarkers and imaging readouts for enrichment, response assessment, and surrogate endpoint potential. The therapeutic landscape spans direct inflammasome inhibitors and IL-1/IL-18 blockade, modulators of upstream metabolic stress, and antifibrotic strategies. Finally, we propose trial frameworks integrating molecular and imaging phenotyping with rhythm and remodeling outcomes, and highlight priorities including assay standardization for pyroptosis and patient selection. By consolidating the inflammasome-fibrosis axis across cardiometabolic conditions, this review defines actionable diagnostic and therapeutic nodes to inform mechanism-guided clinical studies.