Neutrophil Extracellular Traps in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Targets

Abstract: Heart failure (HF) is a clinical syndrome characterized by myocardial remodeling, pathological fibrosis, and chronic sterile inflammation. Within the pathophysiological network of HF and its complex comorbidities, neutrophil extracellular traps (NETs) have been identified as key pathological mediators driving tissue damage. This review aims to explore the regulatory mechanisms of NETs in the progression of heart failure (HF) and their cross-organ pathological effects, and to summarize the latest research advances in NET-targeted interventions for the treatment of HF. NETs are reticular structures composed of antimicrobial proteins, such as myeloperoxidase (MPO) and histones, attached to a decondensed DNA scaffold. Under pathological conditions, excessive NET release and impaired clearance trigger inflammatory cascades. Aberrant NETs formation significantly promotes cardiac remodeling and pathological fibrosis by mediating immunothrombosis, inducing cardiomyocyte apoptosis, and activating fibroblasts.NETs serve as a critical pathophysiological link connecting HF to systemic comorbidities. Therapeutic strategies targeting NETs primarily include inhibiting PAD4 or associated signaling axes to block NETs formation, utilizing enzymatic reactions to facilitate NETs clearance, uncovering the novel potential of established clinical agents, and employing nanotechnology-based precision delivery systems. These findings offer new avenues for precision immunotherapy in HF and highlight considerable potential for clinical translation. Keywords: heart failure, neutrophil extracellular traps, pathology, inflammation, therapeutic targets