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N6-methyladenosine (m<jats:sup>6<\/jats:sup>A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I\/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m<jats:sup>6<\/jats:sup>A influences acute I\/R injury responses remain elusive. Our study reveals that the expression of key I\/R pathogenesis pathways positively correlates with the expression of m<jats:sup>6<\/jats:sup>A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m<jats:sup>6<\/jats:sup>A, results in bidirectional changes in oxidative stress response\u00a0and neuronal viability under I\/R conditions. We have identified <jats:italic>p53<\/jats:italic> mRNA as a critical target of m<jats:sup>6<\/jats:sup>A methylation and YTHDF1, driving the translation of p53 protein in a context- and m<jats:sup>6<\/jats:sup>A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m<jats:sup>6<\/jats:sup>A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I\/R injury.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical abstract<\/jats:bold>\n          <\/jats:p>\n          <jats:p>m<jats:sup>6<\/jats:sup>A-dependent YTHDF1 binding to <jats:italic>p53<\/jats:italic> mRNA promotes its translation and ferroptosis during acute cerebral ischemia\/reperfusion (I\/R)<\/jats:p>\n          <jats:p>Critical points:<\/jats:p>\n          <jats:p>\u2022 I\/R upregulates YTHDF1 expression and its binding to m<jats:sup>6<\/jats:sup>A-modfied <jats:italic>p53<\/jats:italic> mRNA;<\/jats:p>\n          <jats:p>\u2022 Binding by YTHDF1 promotes translation of <jats:italic>p53<\/jats:italic> mRNA and induces ferroptosis;<\/jats:p>\n          <jats:p>\u2022 AAV-mediated knockdown of YTHDF1 alleviates I\/R-induced neuronal damage in acute phase.<\/jats:p>","DOI":"10.1007\/s10565-025-10061-3","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T09:00:43Z","timestamp":1751360443000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["YTHDF1 promotes p53 translation and induces ferroptosis during acute cerebral ischemia\/reperfusion through m6A-dependent binding"],"prefix":"10.1007","volume":"41","author":[{"given":"Xinyu","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aixia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengmin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan Ohtan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"10061_CR1","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/s41419-018-0282-x","volume":"9","author":"MH Bao","year":"2018","unstructured":"Bao MH, Szeto V, Yang BB, Zhu SZ, Sun HS, Feng ZP. 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