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<p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) and 5-methylcytosine (m<sup>5</sup>C) are dynamic and reversible RNA modifications that play important roles in cardiovascular diseases (CVDs). By regulating RNA stability, splicing, transport, translation, and degradation, m<sup>6</sup>A and m<sup>5</sup>C shape key pathological processes including endothelial dysfunction, inflammation, apoptosis, fibrosis, impaired contractility, and metabolic remodeling. Core regulators, including METTL3, METTL14, fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and YTH family proteins for m<sup>6</sup>A, as well as NSUN2, DNMT2, TET2, and ALYREF YBX1 for m<sup>5</sup>C related pathways, display disease stage specific and cell type-specific patterns across atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease, highlighting their potential as diagnostic and prognostic biomarkers. Therapeutically, pharmacological modulation of writers and erasers, adeno-associated virus-based gene delivery, and stem cell-based strategies show encouraging preclinical efficacy, while lifestyle interventions such as exercise may optimize the cardiac RNA methylation landscape. In addition, emerging RNA methylation marks, including N¹-methyladenosine <b>(</b>m<sup>1</sup>A),7-methylguanosine (m<sup>7</sup>G), N⁶,2’-O-dimethyladenosine (m<sup>6</sup>Am), and oxidative cytosine derivatives such as 5-hydroxymethylcytosine (hm<sup>5</sup>C) and 5-formylcytosine (f<sup>5</sup>C), further expand the RNA modification landscape of cardiovascular remodeling by linking cap-dependent translation, mitochondrial protein synthesis, and stress adaptation. However, major challenges remain, including resolving RNA methylation dynamics at single-nucleotide and single-cell resolution, integrating RNA methylation with other regulatory layers, and achieving precise cardiac delivery with durable safety. With advances in multi-omics, spatial mapping, nanomedicine, and translational research, targeting RNA methylation offers a promising paradigm for improved diagnosis, risk stratification, and personalized therapy in cardiovascular disease.</p> Graphical Abstract <p></p>

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RNA methylation in cardiovascular remodeling: Molecular mechanisms, biomarkers, and therapeutic strategies

  • 期刊论文

  • 发表日期：

    2026年5月5日

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  • Huilin Li,
  • Qiming Fan,
  • Jiajun Sang,
  • Chengxia Kan,
  • Xiaodong Sun,
  • Kexin Zhang

摘要

N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are dynamic and reversible RNA modifications that play important roles in cardiovascular diseases (CVDs). By regulating RNA stability, splicing, transport, translation, and degradation, m6A and m5C shape key pathological processes including endothelial dysfunction, inflammation, apoptosis, fibrosis, impaired contractility, and metabolic remodeling. Core regulators, including METTL3, METTL14, fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and YTH family proteins for m6A, as well as NSUN2, DNMT2, TET2, and ALYREF YBX1 for m5C related pathways, display disease stage specific and cell type-specific patterns across atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease, highlighting their potential as diagnostic and prognostic biomarkers. Therapeutically, pharmacological modulation of writers and erasers, adeno-associated virus-based gene delivery, and stem cell-based strategies show encouraging preclinical efficacy, while lifestyle interventions such as exercise may optimize the cardiac RNA methylation landscape. In addition, emerging RNA methylation marks, including N¹-methyladenosine (m1A),7-methylguanosine (m7G), N⁶,2’-O-dimethyladenosine (m6Am), and oxidative cytosine derivatives such as 5-hydroxymethylcytosine (hm5C) and 5-formylcytosine (f5C), further expand the RNA modification landscape of cardiovascular remodeling by linking cap-dependent translation, mitochondrial protein synthesis, and stress adaptation. However, major challenges remain, including resolving RNA methylation dynamics at single-nucleotide and single-cell resolution, integrating RNA methylation with other regulatory layers, and achieving precise cardiac delivery with durable safety. With advances in multi-omics, spatial mapping, nanomedicine, and translational research, targeting RNA methylation offers a promising paradigm for improved diagnosis, risk stratification, and personalized therapy in cardiovascular disease.

Graphical Abstract