NON-CODING RNA NETWORKS REGULATING NLRP3 INFLAMMASOME ACTIVATION IN NEURODEGENERATIVE AND CARDIOVASCULAR DISEASES

Abstract

The NLRP3 inflammasome is a critical multiprotein complex that drives inflammatory responses in both neurodegenerative and cardiovascular diseases through caspase-1 activation and subsequent maturation of interleukin-1β and interleukin-18. Emerging evidence demonstrates that non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, function as master regulators of NLRP3 inflammasome signaling by modulating expression of inflammasome components, upstream activators, and downstream effectors. In neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and stroke, dysregulated non-coding RNA networks contribute to microglial activation, neuroinflammation, and neuronal pyroptosis through NLRP3-dependent mechanisms. Similarly, in cardiovascular diseases including atherosclerosis, myocardial infarction, and heart failure, non-coding RNAs regulate macrophage polarization, endothelial dysfunction, and cardiomyocyte death via NLRP3 inflammasome pathways. MicroRNAs such as miR-223, miR-146a, and miR-155 directly target NLRP3 pathway components, while long non-coding RNAs including NEAT1, MALAT1, and HOTAIR function as competing endogenous RNAs that sequester microRNAs and amplify inflammatory signaling. Circular RNAs such as circHIPK3 further modulate NLRP3 activation through miRNA sponging mechanisms. This review synthesizes current understanding of non-coding RNA-mediated regulation of NLRP3 inflammasome activation across neurodegenerative and cardiovascular disease contexts, highlighting shared molecular mechanisms, translational biomarker potential, and therapeutic targeting opportunities. We discuss knowledge gaps, methodological limitations, and future directions for harnessing non-coding RNA networks to modulate NLRP3-driven inflammation in precision medicine approaches.