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However, its role in chemotherapy\u2010related vascular endothelial injury has not yet been elucidated. We found that methyltransferase\u2010like 3 (METTL3) expression was significantly reduced during doxorubicin (DOX)\u2010induced apoptosis of vascular endothelial cells both in\u00a0vivo and in\u00a0vitro, and that silencing of METTL3 further intensified this process. Combined transcriptome and proteome sequencing analyses revealed that the expression levels of interferon\u2010stimulated gene 15 (ISG15) mRNA and protein significantly increased after METTL3 silencing. Methylated RNA immunoprecipitation (meRIP)\u2010quantitative polymerase chain reaction (qPCR) and mRNA stability assays confirmed that METTL3 regulates the expression of ISG15 by methylating the 1,014,147 site on ISG15 RNA, thereby decreasing ISG15 mRNA levels. Silencing ISG15 significantly suppressed DOX\u2010induced endothelial cell apoptosis and dysfunction caused by METTL3 silencing. In summary, our study revealed that METTL3\u2010mediated methylation of ISG15 mRNA is involved in DOX\u2010induced endothelial cell apoptosis and explored potential therapeutic targets for alleviating chemotherapy\u2010associated vascular injury.<\/jats:p>","DOI":"10.1111\/jcmm.70339","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T04:20:16Z","timestamp":1736482816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>METTL3<\/scp>\u2010Mediated <scp>m6A<\/scp> Modification of <scp>ISG15 mRNA<\/scp> Regulates Doxorubicin\u2010Induced Endothelial Cell Apoptosis"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7771-136X","authenticated-orcid":false,"given":"Dongdong","family":"Jian","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences Peking University Health Science Center  Beijing China"},{"name":"Zhengzhou Key Laboratory of Cardiovascular Aging, Henan Province Key Laboratory for Prevention and Treatment of Coronary Heart Disease, National Health Commission key Laboratory of Cardiovascular Regenerative Medicine Central China Fuwai Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital &amp; 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