Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang
{"title":"mettl14介导的pri-miR-5099的m6A甲基化促进心肌梗死中心肌细胞焦亡。","authors":"Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang","doi":"10.1038/s41401-025-01485-y","DOIUrl":null,"url":null,"abstract":"<p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m<sup>6</sup>A modification promotes the development and progression of cardiomyocyte pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1639-1651"},"PeriodicalIF":6.9000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099011/pdf/","citationCount":"0","resultStr":"{\"title\":\"METTL14-mediated m<sup>6</sup>A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.\",\"authors\":\"Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang\",\"doi\":\"10.1038/s41401-025-01485-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m<sup>6</sup>A modification promotes the development and progression of cardiomyocyte pyroptosis.</p>\",\"PeriodicalId\":6942,\"journal\":{\"name\":\"Acta Pharmacologica Sinica\",\"volume\":\" \",\"pages\":\"1639-1651\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099011/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Pharmacologica Sinica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41401-025-01485-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Pharmacologica Sinica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41401-025-01485-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
METTL14-mediated m6A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.
N6-methyladenosine (m6A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m6A modification promotes the development and progression of cardiomyocyte pyroptosis.
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