{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T21:09:40Z","timestamp":1773436180354,"version":"3.50.1"},"reference-count":109,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Macau Science and Technology Development Fund","award":["0021\/2020\/AGJ"],"award-info":[{"award-number":["0021\/2020\/AGJ"]}]},{"name":"Macau Science and Technology Development Fund","award":["0011\/2020\/A1"],"award-info":[{"award-number":["0011\/2020\/A1"]}]},{"name":"Macau Science and Technology Development Fund","award":["0012\/2021\/AMJ"],"award-info":[{"award-number":["0012\/2021\/AMJ"]}]},{"name":"Macau Science and Technology Development Fund","award":["003\/2022\/ALC"],"award-info":[{"award-number":["003\/2022\/ALC"]}]},{"name":"Macau Science and Technology Development Fund","award":["0092\/2022\/A2"],"award-info":[{"award-number":["0092\/2022\/A2"]}]},{"name":"Macau Science and Technology Development Fund","award":["81973320"],"award-info":[{"award-number":["81973320"]}]},{"name":"National Natural Science Foundation of China","award":["0021\/2020\/AGJ"],"award-info":[{"award-number":["0021\/2020\/AGJ"]}]},{"name":"National Natural Science Foundation of China","award":["0011\/2020\/A1"],"award-info":[{"award-number":["0011\/2020\/A1"]}]},{"name":"National Natural Science Foundation of China","award":["0012\/2021\/AMJ"],"award-info":[{"award-number":["0012\/2021\/AMJ"]}]},{"name":"National Natural Science Foundation of China","award":["003\/2022\/ALC"],"award-info":[{"award-number":["003\/2022\/ALC"]}]},{"name":"National Natural Science Foundation of China","award":["0092\/2022\/A2"],"award-info":[{"award-number":["0092\/2022\/A2"]}]},{"name":"National Natural Science Foundation of China","award":["81973320"],"award-info":[{"award-number":["81973320"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>SET and MYND Domain-Containing 2 (Smyd-2), a specific protein lysine methyltransferase (PKMT), influences both histones and non-histones. Its role in cerebral ischemia\/reperfusion (CIR), particularly in ferroptosis\u2014a regulated form of cell death driven by lipid peroxidation\u2014remains poorly understood. This study identifies the expression of Smyd-2 in the brain and investigates its relationship with neuronal programmed cell death (PCD). We specifically investigated how Smyd-2 regulates ferroptosis in CIR through its interaction with the Nuclear Factor Erythroid-2-related Factor-2 (Nrf-2)\/Kelch-like ECH-associated protein (Keap-1) pathway. Smyd-2 knockout protects HT-22 cells from Erastin-induced ferroptosis but not TNF-\u03b1 + Smac-mimetic-induced apoptosis\/necroptosis. This neuroprotective effect of Smyd-2 knockout in HT-22 cells after Oxygen\u2013Glucose Deprivation\/Reperfusion (OGD\/R) was reversed by Erastin. Smyd-2 knockout in HT-22 cells shows neuroprotection primarily via the Nuclear Factor Erythroid-2-related Factor-2 (Nrf-2)\/Kelch-like ECH-associated protein (Keap-1) pathway, despite the concurrent upregulation of Smyd-2 and Nrf-2 observed in both the middle cerebral artery occlusion (MCAO) and OGD\/R models. Interestingly, vivo experiments demonstrated that Smyd-2 knockout significantly reduced ferroptosis and lipid peroxidation in hippocampal neurons following CIR. Moreover, the Nrf-2 inhibitor ML-385 abolished the neuroprotective effects of Smyd-2 knockout, confirming the pivotal role of Nrf-2 in ferroptosis regulation. Cycloheximide (CHX) fails to reduce Nrf-2 expression in Smyd-2 knockout HT-22 cells. Smyd-2 knockout suppresses Nrf-2 lysine methylation, thereby promoting the Nrf-2\/Keap-1 pathway without affecting the PKC-\u03b4\/Nrf-2 pathway. Conversely, Smyd-2 overexpression disrupts Nrf-2 nuclear translocation, exacerbating ferroptosis and oxidative stress, highlighting its dual regulatory role. This study underscores Smyd-2\u2019s potential for ischemic stroke treatment by disrupting the Smyd-2\/Nrf-2-driven antioxidant capacity, leading to hippocampal neuronal ferroptosis. By clarifying the intricate interplay between ferroptosis and oxidative stress via the Nrf-2\/Keap-1 pathway, our findings provide new insights into the molecular mechanisms of CIR and identify Smyd-2 as a promising therapeutic target.<\/jats:p>","DOI":"10.3390\/cells13231969","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T09:21:23Z","timestamp":1732785683000},"page":"1969","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unveiling Smyd-2\u2019s Role in Cytoplasmic Nrf-2 Sequestration and Ferroptosis Induction in Hippocampal Neurons After Cerebral Ischemia\/Reperfusion"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6547-1258","authenticated-orcid":false,"given":"Daohang","family":"Liu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-8041","authenticated-orcid":false,"given":"Yizhun","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 201203, China"},{"name":"School of Pharmacy, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1177\/0271678X18800589","article-title":"The importance of comorbidities in ischemic stroke: Impact of hypertension on the cerebral circulation","volume":"38","author":"Cipolla","year":"2018","journal-title":"J. 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