NLRP3 inflammasome-NETosis crosstalk in hypertensive cardiac remodeling: Cellular mechanisms and therapeutic opportunities.

Hypertensive cardiac remodeling (HCR) encompasses maladaptive structural and functional changes-including cardiomyocyte hypertrophy, myocardial fibrosis, and ventricular dysfunction-that develop in response to chronic pressure overload. Increasing evidence indicates that inflammation is not merely a secondary consequence of hypertensive stress, but a central driver of cardiomyocyte injury, myocardial fibrosis, and ventricular remodeling. Among the inflammatory mechanisms involved, the NLRP3 inflammasome and neutrophil extracellular trap formation, or NETosis, have emerged as interconnected amplifiers of sterile inflammation and hypertensive cardiac remodeling. NLRP3 inflammasome activation promotes caspase-1-dependent maturation of IL-1β and IL-18, pyroptotic cell death, and profibrotic signaling, whereas excessive NETosis releases extracellular DNA, histones, and myeloperoxidase, thereby exacerbating oxidative stress, immune activation, and myocardial injury. These two pathways may form a self-amplifying inflammatory circuit in which inflammasome-derived cytokines promote NETosis, while NET-associated components further activate NLRP3 signaling. In this review, we summarize current evidence on NLRP3 inflammasome-NETosis crosstalk in hypertensive cardiac remodeling, with emphasis on cellular mediators, pathological relevance, and therapeutic intervention points. We also discuss potential strategies targeting this crosstalk, including inflammasome inhibition, suppression of NET formation, NET clearance, and indirect immunometabolic modulation. Finally, we address major translational challenges, including target specificity, therapeutic timing, host-defense impairment, and limited clinical evidence. Understanding NLRP3 inflammasome-NETosis crosstalk may provide new opportunities for inflammation-driven hypertensive cardiac remodeling.