{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:50:21Z","timestamp":1783039821675,"version":"3.54.6"},"reference-count":37,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiaxing Science and Technology Program","award":["2023AY40029"],"award-info":[{"award-number":["2023AY40029"]}]},{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["LQ23H020001"],"award-info":[{"award-number":["LQ23H020001"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82300363"],"award-info":[{"award-number":["82300363"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Zhejiang Province Clinical Key Specialty Construction Project","award":["2024-ZJZK-001"],"award-info":[{"award-number":["2024-ZJZK-001"]}]},{"name":"Jiaxing Clinical Key Specialty Construction Project","award":["2023-JXZK-001"],"award-info":[{"award-number":["2023-JXZK-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Myocardial ischemia-reperfusion (I\/R) injury represents the major obstacle to achieving successful therapeutic outcomes in acute myocardial infarction patients. Fat mass and obesity-associated protein (Fto), an N6-methyladenosine (m6A) RNA demethylase, has been shown to protect cardiomyocytes against oxygen-glucose deprivation\/reperfusion-mediated injury by regulating annexin A1 (Anxa1) expression in vitro. The present study aims to confirm the cardioprotective role of the Fto\/Anxa1 axis using in vivo myocardial I\/R injury models. Methods: Wild-type (WT) and Anxa1 knockout (KO) mice underwent 30-min left coronary artery ligation and 2-h reperfusion after intramyocardial delivery of recombinant adeno-associated virus serotype 9 encoding Fto (adFto) or a control vector (adnull). The effects of Fto overexpression on cardiac function, fibrosis, apoptosis, and inflammatory response were examined using echocardiography, Masson\u2019s trichrome staining, western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemical staining. m6A-RNA immunoprecipitation-quantitative polymerase chain reaction quantified Anxa1 mRNA methylation. Results: Fto overexpression by adFto significantly improved cardiac function, reduced serum creatine kinase-myocardial band and troponin T levels, and alleviated cardiac fibrosis in I\/R-injured WT mice. Mechanistically, Fto weakened I\/R-induced global m6A levels and decreased m6A enrichment on Anxa1 mRNA, thereby enhancing Anxa1 expression. In Anxa1 KO mice, adFto did not confer functional or molecular benefit. Conclusions: Fto enhances Anxa1 and mitigates myocardial I\/R injury with suppression of nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (Nlrp3)-inflammasome signaling in vivo, identifying the Fto-Anxa1 axis as a mechanistic contributor and potential therapeutic target.<\/jats:p>","DOI":"10.31083\/fbl42765","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T04:43:39Z","timestamp":1760157819000},"source":"Crossref","is-referenced-by-count":2,"title":["Fto-Mediated m6A Demethylation of Anxa1 Attenuates Cardiac Ischemia\u2013Reperfusion Injury With Suppression of Nlrp3 Inflammasome Signals"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6183-6571","authenticated-orcid":true,"given":"Chaojie","family":"He","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314000 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6940-645X","authenticated-orcid":true,"given":"Haojie","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314000 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7937-2177","authenticated-orcid":true,"given":"Lijia","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314000 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3365-3962","authenticated-orcid":true,"given":"Hao","family":"Zhang","sequence":"first","affiliation":[{"name":"Rhine-nahr-palatinate Heart and Vascular Center, 55543 Bad Kreuznach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1619-4682","authenticated-orcid":true,"given":"Huilin","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314000 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,9,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Carberry J, Marquis-Gravel G, O\u2019Meara E, Docherty KF. Where Are We With Treatment and Prevention of Heart Failure in Patients Post-Myocardial Infarction? JACC. Heart Failure. 2024; 12: 1157\u20131165.","DOI":"10.1016\/j.jchf.2024.04.025"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Ndrepepa G. Improving myocardial injury, infarct size, and myocardial salvage in the era of primary PCI for STEMI. Coronary Artery Disease. 2015; 26: 341\u2013355.","DOI":"10.1097\/MCA.0000000000000220"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Welt FGP, Batchelor W, Spears JR, Penna C, Pagliaro P, Ibanez B, et al. Reperfusion Injury in Patients With Acute Myocardial Infarction: JACC Scientific Statement. Journal of the American College of Cardiology. 2024; 83: 2196\u20132213.","DOI":"10.1016\/j.jacc.2024.02.056"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Zhang S, Yan F, Luan F, Chai Y, Li N, Wang YW, et al. The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2024; 129: 155649.","DOI":"10.1016\/j.phymed.2024.155649"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Benak D, Kolar F, Hlavackova M. Epitranscriptomic Regulations in the Heart. Physiological Research. 2024; 73: S185\u2013S198.","DOI":"10.33549\/physiolres.935265"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nature Reviews. Molecular Cell Biology. 2019; 20: 608\u2013624.","DOI":"10.1038\/s41580-019-0168-5"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 2015; 526: 591\u2013594.","DOI":"10.1038\/nature15377"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Engel M, Eggert C, Kaplick PM, Eder M, R\u00f6h S, Tietze L, et al. The Role of m6A\/m-RNA Methylation in Stress Response Regulation. Neuron. 2018; 99: 389\u2013403.e9.","DOI":"10.1016\/j.neuron.2018.07.009"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Xu ZY, Jing X, Xiong XD. Emerging Role and Mechanism of the FTO Gene in Cardiovascular Diseases. Biomolecules. 2023; 13: 850.","DOI":"10.3390\/biom13050850"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Yang Y, Ren J, Zhang J, Shi H, Wang J, Yan Y. FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21\/Nrf2 activation in a HuR-dependent m6A manner. Redox Biology. 2024; 70: 103067.","DOI":"10.1016\/j.redox.2024.103067"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Sun F, An C, Liu C, Hu Y, Su Y, Guo Z, et al. FTO represses NLRP3-mediated pyroptosis and alleviates myocardial ischemia-reperfusion injury via inhibiting CBL-mediated ubiquitination and degradation of \u03b2-catenin. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2023; 37: e22964.","DOI":"10.1096\/fj.202201793RR"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Chang X, Zhou S, Liu J, Wang Y, Guan X, Wu Q, et al. Zishen Tongyang Huoxue decoction (TYHX) alleviates sinoatrial node cell ischemia\/reperfusion injury by directing mitochondrial quality control via the VDAC1-\u03b2-tubulin signaling axis. Journal of Ethnopharmacology. 2024; 320: 117371.","DOI":"10.1016\/j.jep.2023.117371"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Jiang Q, Chen X, Gong K, Xu Z, Chen L, Zhang F. M6a demethylase FTO regulates the oxidative stress, mitochondrial biogenesis of cardiomyocytes and PGC-1a stability in myocardial ischemia-reperfusion injury. Redox Report: Communications in Free Radical Research. 2025; 30: 2454892.","DOI":"10.1080\/13510002.2025.2454892"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Kelly L, McGrath S, Rodgers L, McCall K, Tulunay Virlan A, Dempsey F, et al. Annexin-A1: The culprit or the solution? Immunology. 2022; 166: 2\u201316.","DOI":"10.1111\/imm.13455"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"D\u2019Amico M, Di Filippo C, La M, Solito E, McLean PG, Flower RJ, et al. Lipocortin 1 reduces myocardial ischemia-reperfusion injury by affecting local leukocyte recruitment. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2000; 14: 1867\u20131869.","DOI":"10.1096\/fj.99-0602fje"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"La M, D\u2019Amico M, Bandiera S, Di Filippo C, Oliani SM, Gavins FN, et al. 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Journal of Cardiac Failure. 2020; 26: 727\u2013732.","DOI":"10.1016\/j.cardfail.2020.05.012"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"He C, Fan H, Zhu C, Huang Y. The up-regulation of ANXA1 by FTO-dependent demethylation alleviates NLRP3-mediated pyroptosis and inflammation in myocardial ischemia\u2013reperfusion injury. Molecular & Cellular Toxicology. 2025; 1\u201312.","DOI":"10.1007\/s13273-025-00513-6"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Deng F, Zhang LQ, Wu H, Chen Y, Yu WQ, Han RH, et al. Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1\/ACE2 axis through GPR41. International Journal of Biological Sciences. 2022; 18: 858\u2013872.","DOI":"10.7150\/ijbs.67724"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif.). 2001; 25: 402\u2013408.","DOI":"10.1006\/meth.2001.1262"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Stougiannou TM, Christodoulou KC, Koufakis T, Mitropoulos F, Mikroulis D, Mazer CD, et al. Progenitor Cell Function and Cardiovascular Remodelling Induced by SGLT2 Inhibitors. Frontiers in Bioscience (Landmark Edition). 2024; 29: 145.","DOI":"10.31083\/j.fbl2904145"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Borst O, Ochmann C, Sch\u00f6nberger T, Jacoby C, Stellos K, Seizer P, et al. Methods employed for induction and analysis of experimental myocardial infarction in mice. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2011; 28: 1\u201312.","DOI":"10.1159\/000331708"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"De Villiers C, Riley PR. Mouse models of myocardial infarction: comparing permanent ligation and ischaemia-reperfusion. Disease Models & Mechanisms. 2020; 13: dmm046565.","DOI":"10.1242\/dmm.046565"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Su X, Shen Y, Jin Y, Kim IM, Weintraub NL, Tang Y. Aging-Associated Differences in Epitranscriptomic m6A Regulation in Response to Acute Cardiac Ischemia\/Reperfusion Injury in Female Mice. Frontiers in Pharmacology. 2021; 12: 654316.","DOI":"10.3389\/fphar.2021.654316"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Wen C, Lan M, Tan X, Wang X, Zheng Z, Lv M, et al. GSK3\u03b2 Exacerbates Myocardial Ischemia\/Reperfusion Injury by Inhibiting Myc. Oxidative Medicine and Cellular Longevity. 2022; 2022: 2588891.","DOI":"10.1155\/2022\/2588891"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Ke WL, Huang ZW, Peng CL, Ke YP. m6A demethylase FTO regulates the apoptosis and inflammation of cardiomyocytes via YAP1 in ischemia-reperfusion injury. Bioengineered. 2022; 13: 5443\u20135452.","DOI":"10.1080\/21655979.2022.2030572"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Singh J, Jackson KL, Tang FS, Fu T, Nowell C, Salimova E, et al. The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2024; 38: e23457.","DOI":"10.1096\/fj.202301802R"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Qi M, Huang H, Li Z, Quan J, Wang J, Huang F, et al. Qingxin Jieyu Granule alleviates myocardial infarction through inhibiting neutrophil extracellular traps via activating ANXA1\/FPR2 axis. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2024; 135: 156147.","DOI":"10.1016\/j.phymed.2024.156147"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Chen D, Liang X, Zhang L, Zhang J, Gao L, Yan D, et al. E3 Ubiquitin Ligase FBXO32 Promotes LPS-Induced Cardiac Injury by Regulating ANXA1\/PI3K\/AKT Signaling. Inflammation. 2025.  (online ahead of print)","DOI":"10.1007\/s10753-025-02273-w"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Qin S, Ren Y, Feng B, Wang X, Liu J, Zheng J, et al. ANXA1sp Protects against Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death via SIRT3-Mediated p53 Deacetylation. Mediators of Inflammation. 2023; 2023: 6638929.","DOI":"10.1155\/2023\/6638929"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Francisco J, Del Re DP. Inflammation in Myocardial Ischemia\/Reperfusion Injury: Underlying Mechanisms and Therapeutic Potential. Antioxidants (Basel, Switzerland). 2023; 12: 1944.","DOI":"10.3390\/antiox12111944"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Xiang Q, Yi X, Zhu XH, Wei X, Jiang DS. Regulated cell death in myocardial ischemia-reperfusion injury. Trends in Endocrinology and Metabolism: TEM. 2024; 35: 219\u2013234.","DOI":"10.1016\/j.tem.2023.10.010"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J, et al. Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends in Cardiovascular Medicine. 2023; 33: 357\u2013366.","DOI":"10.1016\/j.tcm.2022.02.005"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Chen L, Mao LS, Xue JY, Jian YH, Deng ZW, Mazhar M, et al. Myocardial ischemia-reperfusion injury: The balance mechanism between mitophagy and NLRP3 inflammasome. Life Sciences. 2024; 355: 122998.","DOI":"10.1016\/j.lfs.2024.122998"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Shen S, Wang Z, Sun H, Ma L. Role of NLRP3 Inflammasome in Myocardial Ischemia-Reperfusion Injury and Ventricular Remodeling. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2022; 28: e934255.","DOI":"10.12659\/MSM.934255"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Galv\u00e3o I, de Carvalho RVH, Vago JP, Silva ALN, Carvalho TG, Antunes MM, et al. The role of annexin A1 in the modulation of the NLRP3 inflammasome. 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