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However, the regulatory mechanisms underlying ferroptosis in MI\/R remain incompletely understood. Here, we investigated the role of lactate-mediated YTHDF2 regulation in cardiomyocyte ferroptosis. A murine ischemia\u2013reperfusion (I\/R) model and an H9C2 hypoxia\/reoxygenation (H\/R) model were established. Biochemical assays revealed elevated lactate levels in MI\/R hearts, accompanied by increased infarct size, enhanced structural damage, and elevated Fe\u00b2\u207a and creatine kinase-MB (CK-MB) levels. Lactate treatment promoted YTHDF2 lactylation and upregulated its expression in cardiomyocytes. Mechanistically, YTHDF2 bound to ferritin heavy chain 1 (FTH1) mRNA and reduced its stability through m6A-dependent degradation, thereby promoting ferroptosis. Knockdown of YTHDF2 suppressed ferroptosis, an effect reversed by FTH1 reduction. These findings identify lactate-induced YTHDF2 lactylation as a key driver of cardiomyocyte ferroptosis and reveal a novel mechanism exacerbating MI\/R injury, suggesting that targeting this pathway may represent a potential therapeutic strategy.<\/jats:p>","DOI":"10.1038\/s41598-026-35130-3","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T17:43:54Z","timestamp":1767894234000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lactate regulates the YTHDF2-FTH1 axis to promote cardiomyocyte ferroptosis and aggravate myocardial ischemia-reperfusion injury"],"prefix":"10.1038","volume":"16","author":[{"given":"Zhonghao","family":"Xiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bitao","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4306-1818","authenticated-orcid":false,"given":"Yadong","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0072-8037","authenticated-orcid":false,"given":"Chengliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"35130_CR1","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","volume":"17","author":"G Heusch","year":"2020","unstructured":"Heusch, G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 17, 773\u2013789. https:\/\/doi.org\/10.1038\/s41569-020-0403-y (2020).","journal-title":"Nat. Rev. Cardiol."},{"key":"35130_CR2","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1016\/j.gendis.2022.02.012","volume":"10","author":"Y Yang","year":"2023","unstructured":"Yang, Y. & Lin, X. Potential relationship between autophagy and ferroptosis in myocardial ischemia\/reperfusion injury. Genes Dis. 10, 2285\u20132295. https:\/\/doi.org\/10.1016\/j.gendis.2022.02.012 (2023).","journal-title":"Genes Dis."},{"key":"35130_CR3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10495-022-01786-1","volume":"28","author":"SV Popov","year":"2023","unstructured":"Popov, S. V. et al. Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis: Int. J. Program. cell. Death. 28, 55\u201380. https:\/\/doi.org\/10.1007\/s10495-022-01786-1 (2023).","journal-title":"Apoptosis: Int. J. Program. cell. Death"},{"key":"35130_CR4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/s41421-023-00622-3","volume":"10","author":"S Liu","year":"2024","unstructured":"Liu, S. et al. The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5\/MAVS\/NLRP3 axis. Cell. Discovery. 10, 24. https:\/\/doi.org\/10.1038\/s41421-023-00622-3 (2024).","journal-title":"Cell. Discovery"},{"key":"35130_CR5","doi-asserted-by":"publisher","first-page":"9929687","DOI":"10.1155\/2021\/9929687","volume":"2021","author":"WK Zhao","year":"2021","unstructured":"Zhao, W. K., Zhou, Y., Xu, T. T. & Wu, Q. Ferroptosis: Opportunities and challenges in myocardial ischemia-reperfusion injury. Oxidative Med. Cell. Longev. 2021, 9929687. https:\/\/doi.org\/10.1155\/2021\/9929687 (2021).","journal-title":"Oxidative Med. Cell. Longev."},{"key":"35130_CR6","doi-asserted-by":"publisher","first-page":"7038","DOI":"10.1111\/febs.16059","volume":"289","author":"J Liu","year":"2022","unstructured":"Liu, J., Kang, R. & Tang, D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 289, 7038\u20137050. https:\/\/doi.org\/10.1111\/febs.16059 (2022).","journal-title":"FEBS J."},{"key":"35130_CR7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","volume":"31","author":"D Tang","year":"2021","unstructured":"Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. 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