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METTL14-mediated m6A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction

Acta Pharmacologica Sinica volume 46, pages 1639–1651 (2025)Cite this article

Abstract

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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Fig. 1: The effect of miR-5099-3p deficiency on cardiac protection.
Fig. 2: m6A modification regulated the processing of miR-5099-3p.
Fig. 3: METTL14 regulated the expression of miR-5099-3p by binding to DGCR8.
Fig. 4: Knock-down of METTL14 protects the heart from MI injury.
Fig. 5: ELF1 serves as the downstream target negatively regulated by miR-5099-3p.
Fig. 6: ELF1 interacts with and negatively regulates Caspase-1 and GSDMD.
Fig. 7

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References

  1. Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147:e93–e621.

    Article  PubMed  Google Scholar 

  2. Eggers KM, Jernberg T, Lindahl B. Risk-associated management disparities in acute myocardial infarction. Sci Rep. 2021;11:24488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jung M, Dodsworth M, Thum T. Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction. Basic Res Cardiol. 2018;114:4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yee K, Malliaras K, Kanazawa H, Tseliou E, Cheng K, Luthringer DJ, et al. Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy. PLoS One. 2014;9:e113805.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cheng K, Malliaras K, Shen D, Tseliou E, Ionta V, Smith J, et al. Intramyocardial injection of platelet gel promotes endogenous repair and augments cardiac function in rats with myocardial infarction. J Am Coll Cardiol. 2012;59:256–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li J, Sun S, Zhu D, Mei X, Lyu Y, Huang K, et al. Inhalable stem cell exosomes promote heart repair after myocardial infarction. Circulation. 2024;150:710–23.

    Article  CAS  PubMed  Google Scholar 

  7. Sun T, Dong YH, Du W, Shi CY, Wang K, Tariq MA, et al. The role of MicroRNAs in myocardial infarction: from molecular mechanism to clinical application. Int J Mol Sci. 2017;18:745.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Xu YJ, Zheng L, Hu YW, Wang Q. Pyroptosis and its relationship to atherosclerosis. Clin Chim Acta Int J Clin Chem. 2018;476:28–37.

    Article  CAS  Google Scholar 

  9. Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:143–57.

    Article  CAS  PubMed  Google Scholar 

  10. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–6.

    Article  CAS  PubMed  Google Scholar 

  11. Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol Immunol. 2021;18:1106–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gao F, Kataoka M, Liu N, Liang T, Huang ZP, Gu F, et al. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun. 2019;10:1802.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Horváth M, Horváthová V, Hájek P, Štěchovský C, Honěk J, Šenolt L, et al. MicroRNA-331 and microRNA-151-3p as biomarkers in patients with ST-segment elevation myocardial infarction. Sci Rep. 2020;10:5845.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yang L, Wang B, Zhou Q, Wang Y, Liu X, Liu Z, et al. MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7. Cell Death Dis. 2018;9:769.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Qian L, Zhao Q, Yu P, LĂĽ J, Guo Y, Gong X, et al. Diagnostic potential of a circulating miRNA model associated with therapeutic effect in heart failure. J Transl Med. 2022;20:267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yao W, Han X, Ge M, Chen C, Xiao X, Li H, et al. N6-methyladenosine (m6A) methylation in ischemia-reperfusion injury. Cell Death Dis. 2020;11:478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, et al. Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med. 2020;46:1958–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qian B, Wang P, Zhang D, Wu L. m6A modification promotes miR-133a repression during cardiac development and hypertrophy via IGF2BP2. Cell Death Discov. 2021;7:157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Han SH, Choe J. Diverse molecular functions of m6A mRNA modification in cancer. Exp Mol Med. 2020;52:738–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Batista PJ. The RNA modification N6-methyladenosine and its implications in human disease. Genom Proteom Bioinforma. 2017;15:154–63.

    Article  CAS  Google Scholar 

  21. Chen L, Zhang M, Yang X, Wang Y, Huang T, Li X, et al. Methyl-CpG-binding 2 K271 lactylation-mediated M2 macrophage polarization inhibits atherosclerosis. Theranostics. 2024;14:4256–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xu Y, Yan J, Tao Y, Qian X, Zhang C, Yin L, et al. Pituitary hormone α-MSH promotes tumor-induced myelopoiesis and immunosuppression. Science. 2022;377:1085–91.

    Article  CAS  PubMed  Google Scholar 

  23. Liu Y, Li J, Xu N, Yu H, Gong L, Li Q, et al. Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice. J Adv Res. 2022;39:275–89.

    Article  CAS  PubMed  Google Scholar 

  24. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015;4:e05005.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Messeguer X, Escudero R, Farré D, Núñez O, Martínez J, Albà MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18:333–4.

    Article  CAS  PubMed  Google Scholar 

  26. Wan T, Li X, Li Y. The role of TRIM family proteins in autophagy, pyroptosis, and diabetes mellitus. Cell Biol Int. 2021;45:913–26.

    Article  CAS  PubMed  Google Scholar 

  27. Wu J, Sun J, Meng X. Pyroptosis by caspase-11 inflammasome-Gasdermin D pathway in autoimmune diseases. Pharmacol Res. 2021;165:105408.

    Article  CAS  PubMed  Google Scholar 

  28. McKenzie BA, Dixit VM, Power C. Fiery cell death: pyroptosis in the central nervous system. Trends Neurosci. 2020;43:55–73.

    Article  CAS  PubMed  Google Scholar 

  29. Ong SB, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA, et al. Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther. 2018;186:73–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sasaki T, Shimazawa M, Kanamori H, Yamada Y, Nishinaka A, Kuse Y, et al. Effects of progranulin on the pathological conditions in experimental myocardial infarction model. Sci Rep. 2020;10:11842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhu D, Liu S, Huang K, Wang Z, Hu S, Li J, et al. Intrapericardial exosome therapy dampens cardiac injury via activating Foxo3. Circ Res. 2022;131:e135–e50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Luo L, Li Y, Bao Z, Zhu D, Chen G, Li W, et al. Pericardial delivery of SDF-1α puerarin hydrogel promotes heart repair and electrical coupling. Adv Mater. 2024;36:e2302686.

    Article  PubMed  Google Scholar 

  33. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao Y, Shi J, Shao F. Inflammatory caspases: activation and cleavage of Gasdermin-D in vitro and during pyroptosis. Methods Mol Biol. 2018;1714:131–48.

    Article  CAS  PubMed  Google Scholar 

  35. Bian Y, Li X, Pang P, Hu XL, Yu ST, Liu YN, et al. Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis. Acta Pharmacol Sin. 2020;41:319–26.

    Article  CAS  PubMed  Google Scholar 

  36. Gao Y, Li H, Que Y, Chen W, Huang SY, Liu W, et al. Lycium barbarum polysaccharides (LBP) suppresses hypoxia/reoxygenation (H/R)-induced rat H9C2 cardiomyocytes pyroptosis via Nrf2/HO-1 signaling pathway. Int J Biol Macromol. 2024;280:135924.

    Article  CAS  PubMed  Google Scholar 

  37. Shi H, Gao Y, Dong Z, Yang J, Gao R, Li X, et al. GSDMD-mediated cardiomyocyte pyroptosis promotes myocardial I/R injury. Circ Res. 2021;129:383–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alarcón CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015;519:482–5.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Alsharafi WA, Xiao B, Abuhamed MM, Luo Z. miRNAs: biological and clinical determinants in epilepsy. Front Mol Neurosci. 2015;8:59.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pan W, Zhong Y, Cheng C, Liu B, Wang L, Li A, et al. MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy. PLoS One. 2013;8:e53950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ouyang Z, Wei K. miRNA in cardiac development and regeneration. Cell Regen. 2021;10:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med. 2015;7:279ra38.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    Article  CAS  PubMed  Google Scholar 

  44. Deng X, Su R, Weng H, Huang H, Li Z, Chen J. RNA N6-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28:507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, et al. Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 2019;10:1858.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary microRNA processing. Hepatology. 2017;65:529–43.

    Article  CAS  PubMed  Google Scholar 

  48. Song D, Hou J, Wu J, Wang J. Role of N6-methyladenosine RNA modification in cardiovascular disease. Front Cardiovasc Med. 2021;8:659628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kmietczyk V, Riechert E, Kalinski L, Boileau E, Malovrh E, Malone B, et al. m6A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Sci Alliance. 2019;2:e201800233.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Dorn LE, Lasman L, Chen J, Xu X, Hund TJ, Medvedovic M, et al. The N6-methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation. 2019;139:533–45.

    Article  CAS  PubMed  Google Scholar 

  51. Huang X, Brown C, Ni W, Maynard E, Rigby AC, Oettgen P. Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Blood. 2006;107:3153–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen CH, Su LJ, Tsai HT, Hwang CF. ELF-1 expression in nasopharyngeal carcinoma facilitates proliferation and metastasis of cancer cells via modulation of CCL2/CCR2 signaling. Cancer Manag Res. 2019;11:5243–54.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Cheng M, Zeng Y, Zhang T, Xu M, Li Z, Wu Y. Transcription factor ELF1 activates MEIS1 transcription and then regulates the GFI1/FBW7 axis to promote the development of glioma. Mol Ther Nucleic Acids. 2021;23:418–30.

    Article  CAS  PubMed  Google Scholar 

  54. Budka JA, Ferris MW, Capone MJ, Hollenhorst PC. Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance. Genes Cancer. 2018;9:198–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Madison BJ, Clark KA, Bhachech N, Hollenhorst PC, Graves BJ, Currie SL. Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites. J Biol Chem. 2018;293:18624–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jian D, Wang Y, Jian L, Tang H, Rao L, Chen K, et al. METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications. Theranostics. 2020;10:8939–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang L, Wang J, Yu P, Feng J, Xu GE, Zhao X, et al. METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury. Nat Commun. 2022;13:6762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The mechanism diagram was created with BioRender.com.

This work was supported by Key Project of Natural Science Foundation of Heilongjiang Province (ZD2023H001 to NW); the National Natural Science Foundation of China (82170284 to NW, 82370328 to JML); HMU Marshal Initiative Funding (HMUMIF-21026); and China Postdoctoral Science Foundation (2023T160173 to JML).

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  1. These authors contributed equally: Hang Yu, Qing-sui Li, Jun-nan Guo.

Authors and Affiliations

  1. Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD)), College of Pharmacy, Harbin Medical University, Harbin, 150081, China

    Hang Yu, Qing-sui Li, 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

  2. Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150040, China

    Jun-nan Guo

  3. Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China

    Ben-zhi Cai, Jia-min Li & Ning Wang

  4. Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, 150080, China

    Ben-zhi Cai, Jia-min Li & Ning Wang

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  1. Hang Yu
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Contributions

HY, QSL, and JNG: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization. ZZ, XZL, and YNL: Methodology, Data curation. QSL, LQ, XS, QWZ, YDX, and LLG: Methodology, Data curation, Formal analysis. QSL, JNG, NX, ML, WSZ and XMZ: Methodology. WYZ, YJY, XMC, ZZ, WL, and HXW: Data curation, Validation. NW, JML, and BZC: Supervision, Conceptualization, Funding acquisition, Writing – review & editing. All authors read and approved the final manuscript.

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Correspondence to Ben-zhi Cai, Jia-min Li or Ning Wang.

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Yu, H., Li, Qs., Guo, Jn. et al. METTL14-mediated m6A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction. Acta Pharmacol Sin 46, 1639–1651 (2025). https://doi.org/10.1038/s41401-025-01485-y

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