Yassine Ballout

Background:  Cardiovascular diseases such as atrial fibrillation (AF), heart failure, and pulmonary arterial hypertension (PAH) are characterized by pathologic remodeling driven by maladaptive inflammation, disrupted calcium handling, and transcriptional dysregulation. Recent discoveries in epitranscriptomics have shown that RNA modifications, specifically N6-methyladenosine (m6A), play a pivotal role in regulating post-transcriptional gene expression in these conditions. The methyltransferase METTL3, which catalyzes the addition of m6A marks, dynamically regulates transcript stability, splicing, localization, and translation. Dysregulation of METTL3 and m6A signaling is now increasingly recognized as a key driver of cardiovascular pathophysiology and a potential avenue for therapeutic intervention.¹⁻⁴

Objective:  This review aims to evaluate how METTL3-mediated m6A methylation regulates cardiovascular remodeling and how targeting this pathway may present a novel therapeutic strategy in heart disease.

Search Methods:  A literature search was conducted using PubMed and Google Scholar (2019–2025) with the terms “METTL3,” “m6A methylation,” “cardiac remodeling,” “pulmonary hypertension,” and “atrial fibrillation.” Studies selected included translational and preclinical models that investigated m6A regulation in cardiomyocytes under cardiovascular stress.

Results:  METTL3 functions as a central integrator of cardiac stress responses, coordinating molecular remodeling across diverse disease states. In cardiomyocytes, METTL3-mediated m6A methylation preserves cardiac function by regulating the expression of stress-responsive transcripts. Its upregulation in early hypertrophic adaptation supports concentric growth while maintaining contractility, whereas its loss leads to eccentric remodeling accompanied by systolic dysfunction.² These outcomes are linked to altered m6A enrichment on transcripts related to kinase signaling and structural proteins, reflecting a shift from compensatory to maladaptive remodeling. At the same time, METTL3 suppresses autophagy in ischemic stress by destabilizing TFEB transcripts, a master regulator of lysosomal biogenesis.³ Loss of METTL3 in this context permits TFEB accumulation, enhancing autophagic flux and suggesting that METTL3 tunes cellular survival pathways depending on energetic demand.  The balance of m6A deposition and removal is further evidenced by the role of the demethylase FTO, which stabilizes transcripts encoding calcium-handling proteins like SERCA2a and RYR2, supporting proper excitation–contraction coupling during cardiac repair.⁴,⁵ In AF, decreased METTL3 disrupts this balance, leading to aberrant calcium cycling via enhanced PCDHGA10-SERCA2a activity and increased arrhythmogenic potential.¹ This loss of METTL3 is mediated by CREB1/USP9X signaling and reflects a breakdown in normal epitranscriptomic regulation.  Beyond cardiomyocytes, METTL3 regulates immune-mediated cardiac remodeling. In PAH models, METTL3 inhibition via STM2457 reduced right ventricular pressure, pulmonary fibrosis, and macrophage activation—indicating that METTL3 also modulates inflammatory responses contributing to structural heart disease.⁶ Clinical data further show that peripheral blood from coronary artery disease patients exhibits elevated METTL3 and YTHDF1 levels, suggesting that m6A dysregulation is not only tissue-specific but also systemically reflective of cardiovascular burden.⁷

Conclusion: METTL3-directed m6A methylation acts as a versatile and dynamic regulator of cardiovascular health, influencing hypertrophy, autophagy, calcium handling, and inflammation. Its dysregulation contributes to the transition from adaptive to maladaptive remodeling, positioning METTL3 as a compelling therapeutic target. Future research should explore context-dependent modulation of this pathway to restore transcriptomic homeostasis across cardiovascular disease states.

Works Cited

1. Shi J, Zhu XY, Yu RH, et al. Decreased METTL3 in atrial myocytes promotes atrial fibrillation. Europace. 2025;27:euaf021. doi:10.1093/europace/euaf021
2. Dorn LE, Lasman L, Chen J, et al. The m6A mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation. 2019;139(4):533–545. doi:10.1161/CIRCULATIONAHA.118.035232
3. Song H, Feng X, Zhang H, et al. METTL3-mediated m6A RNA methylation regulates autophagy in ischemic heart disease. Autophagy. 2019;15(8):1419–1437. doi:10.1080/15548627.2019.1586246
4. Mathiyalagan P, Adamiak M, Wójciechowska M, et al. FTO-dependent N6-methyladenosine regulates cardiac function during remodeling and repair. Circulation. 2019;139(4):518–532. doi:10.1161/CIRCULATIONAHA.118.033794
5. Mathiyalagan P, Adamiak M, Wójciechowska M, et al. m6A RNA methylation regulates cardiac gene expression and cellular growth. Eur J Heart Fail. 2019;21(10):1335–1345. doi:10.1002/ejhf.1672
6. He C, Ji Y, Zhang Y, et al. Inhibition of Mettl3 by STM2457 and loss of macrophage Mettl3 alleviate pulmonary hypertension and right heart remodeling. Lung. 2025;203:34. doi:10.1007/s00408-025-00788-5
7. Chang Y, Xu C, Li Z, et al. M6A methylation regulators METTL3 and YTHDF1 are upregulated in peripheral blood of coronary heart disease patients and related to disease severity. Front Cardiovasc Med. 2024;11:1442098. doi:10.3389/fcvm.2023.1442098