{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:12:17Z","timestamp":1790266337951,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"BHF","doi-asserted-by":"publisher","award":["FS\/CRTF\/24\/24703"],"award-info":[{"award-number":["FS\/CRTF\/24\/24703"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"BHF","doi-asserted-by":"publisher","award":["FS\/4yPhD\/F\/24\/34210"],"award-info":[{"award-number":["FS\/4yPhD\/F\/24\/34210"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Heart Research UK and SCTS Academic Research Fellowship"},{"name":"van Geest Foundation Heart and Cardiovascular Diseases Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Vein graft disease remains a significant limitation to the long-term patency of venous conduits following coronary artery bypass grafting. Early oxidative stress, triggered by ischaemia\u2013reperfusion injury and haemodynamic changes following the implantation of veins into the arterial circulation, disrupts endothelial integrity and initiates inflammation, apoptosis, and maladaptive remodelling. The KEAP1-NRF2 axis is a central regulator of cellular antioxidant responses; however, its role in the development of vein graft disease remains poorly defined. This narrative review aimed to summarise what is known about NRF2\/KEAP1 signalling in modulating vein graft pathology. Methods: A systematic search of PubMed was conducted to identify original research studies examining the NRF2\/KEAP1 pathway in human saphenous vein tissue in vivo or ex vivo. Narrative synthesis was performed due to limited evidential availability and study heterogeneity. Results: Only one study has directly evaluated NRF2 pathway activation directly in human saphenous vein tissue, and it demonstrated that Protandim (a herbal dietary supplement) treatment increased antioxidant enzyme activity and reduced oxidative stress markers, including superoxide and 4-hydroxynonenal, both known activators of MAPK-dependent smooth muscle proliferation. Adjacent studies in other cells and tissues reveal that NRF2 intersects with multiple pathways central to vein graft pathology: it suppresses NF\u03baB-mediated inflammation, modulates eNOS-NO signalling, inhibits NADPH oxidase expression, regulates MAPK activation, and influences angiogenic responses. However, context-dependent activation of NRF2 under arterial cyclic stretch can paradoxically drive proliferation through p62-mediated KEAP1 sequestration and enhanced glutathione synthesis. Conclusions: The NRF2\/KEAP1 pathway serves as a central integrator of oxidative stress responses that directly intersect with established mechanisms of intimal hyperplasia and pathological angiogenesis. Post-translational KEAP1 inhibition may offer a targeted intervention point to limit these processes. Critical gaps remain regarding our understanding of the role of NRF2 in human saphenous vein under physiological arterial conditions and sex-specific pathway regulation. Mechanistic studies in vein-specific models are essential for advancing our understanding and any potential therapeutic translation.<\/jats:p>","DOI":"10.3390\/cells15060563","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:02:43Z","timestamp":1774026163000},"page":"563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Oxidative Stress and the KEAP1\/NRF2 Axis in Saphenous Vein: Implications for Graft Patency"],"prefix":"10.3390","volume":"15","author":[{"given":"Georgia R.","family":"Layton","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"},{"name":"Department of Cardiac Surgery, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK"},{"name":"Leicester British Heart Foundation Centre of Research Excellence, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Em","family":"Marston","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"},{"name":"Leicester British Heart Foundation Centre of Research Excellence, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Musa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7884-7859","authenticated-orcid":false,"given":"Shameem","family":"Ladak","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"},{"name":"Leicester British Heart Foundation Centre of Research Excellence, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Copperwheat","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2490-955X","authenticated-orcid":false,"given":"Akintoye","family":"Oluwanifemi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-7476","authenticated-orcid":false,"given":"Ibrahim","family":"Antoun","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"},{"name":"Department of Cardiology, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Zakkar","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK"},{"name":"Department of Cardiac Surgery, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, UK"},{"name":"Leicester British Heart Foundation Centre of Research Excellence, Leicester LE3 9QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.coi.2019.05.006","article-title":"The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling","volume":"60","author":"Nauseef","year":"2019","journal-title":"Curr. 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