NLRP3 Inflammasome Activation in Diabetes: A Molecular Nexus between Inflammation and Cardiac Dysfunction

Abstract

Diabetes mellitus (DM) is a major global health concern closely associated with cardiovascular diseases, particularly diabetic cardiomyopathy (DCM), which can develop independently of hypertension or coronary artery disease. Chronic hyperglycemia in DM promotes oxidative stress and inflammation, driving myocardial dysfunction and fibrosis. The NLRP3 inflammasome, a cytosolic multiprotein complex, is a central mediator linking metabolic stress to innate immunity. In both type 1 and type 2 DM, it senses injurious stimuli including mitochondrial reactive oxygen species (ROS), ATP, and advanced glycation end-products (AGEs) activating caspase-1 and triggering the release of pro-inflammatory cytokines IL-1β and IL-18, thereby promoting inflammation and pyroptotic cell death. This review focuses on NLRP3 inflammasome activation in the diabetic heart, emphasizing upstream regulators such as thioredoxin-interacting protein (TXNIP) and NF-κB and downstream consequences including cardiomyocyte death, fibrosis, and contractile maladaptation. Therapeutic approaches targeting NLRP3 range from conventional drugs, including metformin and SGLT2 inhibitors, to specific inhibitors such as MCC950 and colchicine, highlighting their cardioprotective potential. Emerging evidence on microRNA-mediated regulation, exosomal signalling, and inter-organ communication further elucidates how systemic inflammation contributes to heart failure in diabetic patients. Despite progress, significant gaps remain regarding the cell-type specificity, temporal dynamics, and epigenetic control of NLRP3 activation in the diabetic myocardium, limiting translation of preclinical findings into effective therapies. Understanding these mechanisms may enable precise, targeted interventions to mitigate inflammation-driven cardiac injury in DM.