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N6\u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A), the most abundant internal modification of eukaryotic mRNA, is installed by the methyltransferase\u2010like 3 (METTL3)\u2010containing writer complex and regulates RNA fate. Here, we investigated whether METTL3\u2010mediated m\n                    <jats:sup>6<\/jats:sup>\n                    A modification contributes to PANoptosis\u2010like cardiomyocyte death during I\/R injury. In mouse myocardial I\/R and oxygen\u2010glucose deprivation\/reoxygenation (OGD\/R) models, global m\n                    <jats:sup>6<\/jats:sup>\n                    A levels and METTL3 expression were markedly increased. Lactate accumulation was associated with p300\u2010dependent H3K18 lactylation (H3K18la) enrichment at the\n                    <jats:italic>Mettl3<\/jats:italic>\n                    promoter, suggesting a metabolic\u2010epigenetic mechanism for METTL3 transcriptional upregulation. Functionally, METTL3 promoted PANoptosis\u2010related death signaling, strengthened the association of ZBP1 with PANoptosis\u2010related components, and aggravated infarction, adverse remodeling, and cardiac dysfunction, whereas METTL3 deletion or pharmacological inhibition with STM2457 was protective. Mechanistically, METTL3 enhanced m\n                    <jats:sup>6<\/jats:sup>\n                    A modification of\n                    <jats:italic>Egr1<\/jats:italic>\n                    mRNA, thereby increasing EGR1 expression through YTHDF1\u2010mediated translational regulation and IGF2BP2\u2010mediated mRNA stabilization. EGR1 further activated\n                    <jats:italic>Zbp1<\/jats:italic>\n                    transcription, and EGR1 restoration partially reversed the protective effects of METTL3 deficiency. These findings identify a lactate\u2010H3K18la\u2010METTL3\u2010EGR1\u2010ZBP1 axis that drives PANoptosis\u2010like cardiomyocyte death and suggest METTL3 inhibition as a potential strategy against I\/R\u2010induced cardiac injury.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70962","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T07:12:58Z","timestamp":1789974778000},"source":"Crossref","is-referenced-by-count":0,"title":["METTL3\u2010Mediated N6\u2010Methyladenosine Modification Activates the EGR1\u2010ZBP1 Axis to Promote PANoptosis\u2010Like Cardiomyocyte Death in Myocardial Ischemia\u2010Reperfusion Injury"],"prefix":"10.1002","volume":"7","author":[{"given":"Linnan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunming","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianying","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"State Key Laboratory of Cardiovascular Diseases Zhongshan Hospital Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Ischemic Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"},{"name":"National Clinical Research Center for Interventional Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(98)00033-9"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2015.tb00650.x"},{"issue":"13","key":"e_1_2_11_4_1","first-page":"935","article-title":"Targeting Reperfusion Injury in Patients With ST\u2010Segment Elevation Myocardial Infarction: Trials and Tribulations","volume":"38","author":"Hausenloy D. 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