{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:42:31Z","timestamp":1790718151316,"version":"4.1.0"},"reference-count":32,"publisher":"IMR Press","issue":"5","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Hunan Provincial Natural Science Foundation of China","doi-asserted-by":"crossref","award":["2025JJ90026"],"award-info":[{"award-number":["2025JJ90026"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Hunan Provincial Health and Family Planning Commission Project","award":["B202303079716"],"award-info":[{"award-number":["B202303079716"]}]},{"name":"Hunan Provincial Postgraduate Innovation Foundation","award":["CX20220822"],"award-info":[{"award-number":["CX20220822"]}]},{"name":"Hunan Provincial Postgraduate Innovation Foundation","award":["QL2023021"],"award-info":[{"award-number":["QL2023021"]}]},{"name":"Hunan University of Chinese Medicine Undergraduate Research Innovation Fund","award":["2023BKS071"],"award-info":[{"award-number":["2023BKS071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background: Protein p62 interacts with Kelch-like ECH-associated protein 1 (Keap1) competitively, triggering the oxidative stress response mediated by NF-E2-related factor 2 (Nrf2) and preventing ferroptosis in SH-SY5Y cells. Emerging evidence implicates that this regulatory axis may confer neuroprotection against cerebral ischemia-reperfusion injury (CIRI). The current investigation was designed to elucidate whether the p62\/Keap1\/Nrf2 signaling pathway contributes to the amelioration of CIRI through modulation of ferroptosis. Methods: In SH-SY5Y cells, we used an oxygen-glucose deprivation\/reperfusion (OGD\/R) paradigm. In Sprague\u2013Dawley rats, we used a middle cerebral artery occlusion\/reperfusion (MCAO\/R) model. Through these models, we investigated the effects of p62\/Keap1\/Nrf2 pathway activation. Additionally, we used in vitro experiments to analyze ferroptosis markers, cell damage, and the expression of pathway proteins. We injected the p62-overexpressing lentivirus into SH-SY5Y cells and the lateral ventricle of rats subjected to MCAO\/R. Finally, we investigated the effects of an Nrf2 activator and a ferroptosis inhibitor. Results: Nrf2 negatively regulated OGD\/R-triggered ferroptosis in SH-SY5Y cells by increasing glutathione peroxidase 4 (GPX4) expression and decreasing acyl-CoA synthetase long-chain family member 4 (ACSL4) levels. p62 overexpression in cells enhanced the interaction between Keap1 and p62, activating Nrf2 and protecting against OGD\/R\u2013triggered ferroptosis. Activating the p62\/Keap1\/Nrf2 signaling pathway in vivo reduced the brain injury area, decreased neuromotor functional impairment, and decreased the expression of ferroptosis markers in rats. Conclusions: Activation of the p62\/Keap1\/Nrf2 signaling pathway reduces ferroptosis and alleviates CIRI. This protective mechanism provides novel directions for investigating the pathological mechanisms of CIRI.<\/jats:p>","DOI":"10.31083\/jin48011","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T08:26:51Z","timestamp":1780129611000},"source":"Crossref","is-referenced-by-count":2,"title":["Activation of the p62\/Keap1\/Nrf2 Pathway Protects Against Ferroptosis in Cerebral Ischemia-Reperfusion Injury"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4339-4743","authenticated-orcid":true,"given":"Canwen","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China"},{"name":"Department of Hearing and Speech Sciences, School of Medicine and Health, Guangzhou Xinhua University, 510520 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0129-5677","authenticated-orcid":true,"given":"Xuanyi","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1185-5592","authenticated-orcid":true,"given":"Biao","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China"},{"name":"Department of Neurology, People\u2019s Hospital of Ningxiang City, Hunan University of Chinese Medicine, 410600 Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. 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