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N<jats:sup>6<\/jats:sup>\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A) modification, the most abundant reversible methylation modification in eukaryotic mRNAs, plays vital roles in multiple biological processes. Whether and how m<jats:sup>6<\/jats:sup>A modification participates in ionizing radiation (IR)\u2010induced EMT and RILI remain unclear. Here, significantly increased m<jats:sup>6<\/jats:sup>A levels upon IR\u2010induced EMT are detected both in vivo and in vitro. Furthermore, upregulated methyltransferase\u2010like 3 (METTL3) expression and downregulated <jats:italic>\u03b1<\/jats:italic>\u2010ketoglutarate\u2010dependent dioxygenase AlkB homolog 5 (ALKBH5) expression are detected. In addition, blocking METTL3\u2010mediated m<jats:sup>6<\/jats:sup>A modification suppresses IR\u2010induced EMT both in vivo and in vitro. Mechanistically, forkhead box O1 (FOXO1) is identified as a key target of METTL3 by a methylated RNA immunoprecipitation (MeRIP) assay. FOXO1 expression is downregulated by METTL3\u2010mediated mRNA m<jats:sup>6<\/jats:sup>A modification in a YTH\u2010domain family 2 (YTHDF2)\u2010dependent manner, which subsequently activates the AKT and ERK signaling pathways. Overall, the present study shows that IR\u2010responsive METTL3 is involved in IR\u2010induced EMT, probably by activating the AKT and ERK signaling pathways via YTHDF2\u2010dependent FOXO1 m<jats:sup>6<\/jats:sup>A modification, which may be a novel mechanism involved in the occurrence and development of RILI.<\/jats:p>","DOI":"10.1002\/advs.202204784","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T23:06:45Z","timestamp":1681859205000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["METTL3 Mediates Epithelial\u2013Mesenchymal Transition by Modulating FOXO1 mRNA N<sup>6<\/sup>\u2010Methyladenosine\u2010Dependent YTHDF2 Binding: A Novel Mechanism of Radiation\u2010Induced Lung Injury"],"prefix":"10.1002","volume":"10","author":[{"given":"Yang","family":"Feng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardio\u2010Pulmonary Circulation Shanghai Pulmonary Hospital School of Medicine Tongji University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjuan","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Suzhou Science &amp; Technology Town Hospital  Suzhou 215153 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy the Affiliated Jiangyin People's Hospital of Nantong University  Jiangyin 214400 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy the First Affiliated Hospital of Soochow University  Suzhou 215006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5452-5553","authenticated-orcid":false,"given":"Yang","family":"Jiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Medical College of Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1608986"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00877"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2019.03.033"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR2562.1"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.0901412"},{"key":"e_1_2_9_4_1","volume":"2018","author":"Yi M.","year":"2018","journal-title":"Biomed Res. 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