{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:09:31Z","timestamp":1788948571904,"version":"build-2803163510"},"reference-count":234,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Major Project of China","award":["2024ZD0529004"],"award-info":[{"award-number":["2024ZD0529004"]}]},{"name":"Hubei Provincial Science and Technology Project of China","award":["2024BEB008"],"award-info":[{"award-number":["2024BEB008"]}]},{"name":"Tongji Hospital Clinical Research Flagship Program of China","award":["2024TJCR007"],"award-info":[{"award-number":["2024TJCR007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ischemia\u2013reperfusion injury (IRI) is a common form of tissue injury encountered in myocardial infarction, ischemic stroke, solid-organ transplantation, and complex vascular surgery. Timely restoration of blood flow is essential for salvaging ischemic tissues; however, reperfusion itself can induce sterile inflammation and oxidative stress, further compromising microvascular and organ function. Accumulating evidence indicates that alterations in the local microenvironment associated with innate immune responses contribute to this pathological process, with neutrophils representing among the earliest effector cells recruited to injured tissues. In response to danger signals such as damage-associated molecular patterns, neutrophils can release neutrophil extracellular traps (NETs), extracellular web-like structures composed of decondensed chromatin and granular proteins. Extracellular NETs can injure endothelial and parenchymal cells and provide procoagulant scaffolds that contribute to immunothrombosis and local inflammatory responses. Current evidence is derived predominantly from clinical samples and experimental models across different organs. Owing to organ-specific differences in microvascular architecture, cellular composition, and ischemia\u2013reperfusion conditions, the triggers, relative pathological contributions, and responses to NET-targeted interventions are not uniform across tissues. This review first summarizes the intracellular events preceding NET release, the molecular composition of extracellular NETs, and the mechanisms of NET extrusion. We then provide an organ-based synthesis of the local triggers, major injurious effects, and interventional evidence for NETs in the heart, liver, lung, kidney, brain, intestine, limb, and skin, while discussing recurrent pathological features\u2014including microthrombosis, endothelial or barrier injury, and inflammatory amplification\u2014in the context of organ-specific differences and the limitations of the available evidence. In addition, we evaluate therapeutic strategies involving degradation of extracellular NETs and neutralization of their toxic components, inhibition of NET-associated enzymes and upstream signaling pathways, and spatiotemporally targeted delivery, together with the major barriers to clinical translation. Overall, this review provides an organ-structured synthesis of current evidence linking NETs to IRI and offers a framework for understanding their context-dependent pathological roles and for developing organ- and phase-specific therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells15171618","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathophysiological Effects and Targeted Therapy Strategies of Neutrophil Extracellular Traps in Ischemia\u2013Reperfusion Injury"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7387-7477","authenticated-orcid":false,"given":"Yan","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linwu","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willice Wasonga","family":"Omindo","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinji","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ping","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion\u2014From mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. 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