Molecular and Cellular Mechanisms of Neutrophil Extracellular Traps in Cardiovascular Diseases: From NET Formation to Mechanistic Therapeutic Targeting
Rasit Dinc1, Nurittin Ardic2,*
1 INVAMED Medical Innovation Institute, New York, NY, 10007, USA
2 Med-International UK Health Agency Ltd., 95 Paddock Way, Hinckley, Leicestershire, LE10 OBZ, UK
* Corresponding Author: Nurittin Ardic. Email: 
(This article belongs to the Special Issue: NETs: A Decade of Pathological Insights and Future Therapeutic Horizons)
BIOCELL https://doi.org/10.32604/biocell.2025.072337
Received 24 August 2025; Accepted 11 October 2025; Published online 03 November 2025
Abstract
Neutrophil extracellular traps (NETs) have emerged as key mediators of cardiovascular diseases (CVDs), linking innate immune activation to vascular injury, thrombosis, and maladaptive remodeling. This review synthesizes recent insights into the molecular and cellular pathways driving NET formation, including post-translational modifications, metabolic reprogramming, inflammasome signaling, and autophagy. It highlights the role of NETs in atherosclerosis, thrombosis, myocardial ischemia-reperfusion injury, and hypertension, emphasizing common control points such as peptidylarginine deiminase 4 (PAD4)-dependent histone citrullination and nicotinamide adenine dinucleotide phosphate oxidases 2 (NOX2)-mediated oxidative stress. Mechanistic interpretation of circulating biomarkers, including myeloperoxidase (MPO)-DNA complexes, citrullinated histone H3, and cell-free DNA, provides a translational bridge between NET biology and patient stratification. Therapeutic strategies targeting NETs are examined through three main approaches: inhibition of NET initiation, enhancement of chromatin clearance, and neutralization of toxic extracellular components, with attention to both established and emerging interventions. In contrast to previous reviews, this study highlights the novelty of a mechano-therapeutic framework by providing a mechanistic roadmap linking NET formation pathways to therapeutic targeting in cardiovascular disease. Moving forward, integrating mechanistic information with biomarker discovery, precision profiling, and targeted therapies offers innovative strategies to reduce vascular inflammation and improve outcomes in cardiovascular disease.
Keywords
Neutrophil extracellular traps (NETs); cardiovascular disease; peptidylarginine deiminase 4 (PAD4); thrombosis; mechano-therapeutic targeting
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