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Advances in RNA modification in myocardial fibrosis (Review)

  • Authors:
    • Xiaowen Wu
    • Ruiquan Wang
    • Xinzhe Chen
    • Kun Wang
  • View Affiliations / Copyright

    Affiliations: Key Laboratory of Maternal and Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong 250014, P.R. China, Department of Cardiovascular Surgery, Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, Shandong 266021, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 218
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    Published online on: October 7, 2025
       https://doi.org/10.3892/ijmm.2025.5659
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Abstract

Myocardial fibrosis has emerged as a maladaptive remodeling process characterized by dysregulated extracellular matrix (ECM) deposition following cardiac injury. Recent studies have unveiled a complex RNA epitranscriptomic network that is composed of nine major types of RNA modification, namely N6‑methyladenosine (m6A), 1‑methyladenosine (m1A), 5‑methylcytosine (m5C), 7‑methylguanosine (m7G), N4‑acetylcytidine (ac4C), uridylation, adenosine‑to‑inosine (A‑to‑I) editing, pseudouridylation and U34 modification, which dynamically govern fibrotic pathogenesis by fine‑tuning RNA metabolism. Building on this knowledge, the present review proposed a three‑axis regulatory model to account for the underlying mechanism of RNA modification‑driven myocardial fibrosis. First, methylation‑acetylation synergy performs a pivotal role: Methyltransferase‑like (METTL) 3‑mediated m6A and N‑acetyltransferase 10‑driven ac4C modifications converge on the Hippo/Yes‑associated protein and TGF‑β/Smad signaling pathways, thereby exacerbating fibroblast activation and collagen overproduction. Secondly, single‑cell analyses have demonstrated the importance of cell‑type‑specific programming, where METTL1‑catalyzed m7G modifications selectively promote the differentiation of fibroblasts into profibrotic phenotypes, while sparing cardiomyocytes. Thirdly, cross‑modification crosstalk is handled by the RNA‑binding protein human‑antigen R, which integrates m6A, uridylation and A‑to‑I editing signals to regulate ECM dynamics, while the METTL3/fat mass and obesity‑associated protein balance modulates stress‑responsive RNA stability. In spite of these advances, however, the role of RNA modifications in myocardial fibrosis has yet to be fully elucidated. Critical gaps persist in our understanding of the spatial epitranscriptomic landscape, which necessitates the use of single‑cell technologies to map cell‑type‑specific modification patterns. Therapeutically, targeting nodal regulators, such as METTL1 inhibitors, holds promise for precision interventions. Additionally, combinatorial RNA modification signatures may serve as novel diagnostic biomarkers, although for this purpose, validation in clinical cohorts is required. Considered altogether, this framework repositions myocardial fibrosis as an RNA‑centric disorder, thereby challenging the traditional ECM‑centric position and offering fresh mechanistic insights into understanding myocardial fibrosis. Through integrating epitranscriptomic regulation into fibrotic signaling networks, new avenues are opened for therapeutic development in cardiac fibrotic diseases.
View Figures

Figure 1

A graphical depiction of the chemical
modifications occurring in RNA within mammalian cells is provided.
(A) The chemical structures of various RNA modifications, such as
involving mRNAs and microRNAs, as well as (B) Transfer RNAs, are
shown. Specifically, the modification at area 34 of the tRNA
regulates swing pairing, encompassing such as m5C, hm5C, and
others. A-to-I, adenine-to-inosine; m5C,
5-methylcytosine; m6A,
N6-methyladenosine; m1A,
1-methyladenosine, m7G, 7-methylguanosine;
ac4C, N4-acetylcytidine.

Figure 2

The biological functions of
m6A modification are diverse. This reversible process
involves 'writers' such as METTL3 and METTL14, and 'erasers' such
as FTO and ALKBH5 that remove the modification. The 'readers', such
as those with the YTH domain recognize and bind to
m6A-modified RNA, thereby influencing RNA processing and
its transport to the cytoplasm. Ultimately, m6A
modulation controls RNA translation, stability and degradation
within the cytoplasm. m6A,
N6-methyladenosine; METTL,
methyltransferase-like; FTO, fat mass and obesity-associated;
ALKBH5, AlkB homolog 5; YTH, YT521-B homology.

Figure 3

m1A and m5C
modifications. (A) Within the cell nucleus, mRNAs and tRNAs undergo
methylation by enzymes including TRMT6 and TRMT61A. Specifically,
the methylation of m1A on mt-tRNA, rRNA and mRNA is
catalyzed by TRMT10C/TRMT61B. The enzymes FTO and ALKBH1/3/7 are
responsible for controlling the demethylation process.
Functionally, m1A employs various mechanisms to regulate
translation and RNA stability, with YTHDF serving as a potential
'reader' of m1A modifications. (B) Aspartic acid tRNA is a specific
target for methylation by the enzyme TRDMT1. The methyltransferases
NSUN1-6 function as 'writers' of m5C modifications in RNA,
influencing RNA nuclear export, metabolism, and function. Various
proteins, including ALYREF, YBX1 and YTHDF2, have been reported to
serve as 'readers' of m5C modifications. Additionally, TNT2, ALKBH1
are responsible for catalyzing the oxidation of m5C rather than its
elimination. m1A, 1-methyladenosine; m5C,
5-methylcytosine; Mt-mitochondrial; ALKBH1, AlkB homolog 1; YTH,
YT521-B homology; FTO, fat mass and obesity-associated; ALKBH5,
AlkB homolog 5; YTH, YT521-B homology; rRNA, ribosomal RNA.

Figure 4

m7G and ac4C
modifications. (A) In the nucleus, METTL1-WDR4 serves as the
'reader' for m7G modifications in mRNAs, pre-miRNAs and
tRNAs. WBSCR22-TRMT112 is responsible for reading 18S rRNA. The
mammalian mRNA cap methyltransferase complex, RNMT-RAM, on the
other hand, primarily targets mRNA for m7G modification.
m7G has various roles in enhancing translation rates, in
accelerating RNA export, in contributing to ribosome synthesis and
in facilitating the maturation of miRNAs. (B) Within the nucleus,
NAT10 and THUMPD1 primarily function as enzymes that catalyze
ac4C modifications on rRNAs, tRNAs and mRNAs. These
modifications are associated with translation efficiency, ribosome
biosynthesis, and mRNA stability, respectively. METTL,
methyltransferase-like; tRNAs m7G, 7-methylguanosine;
ac4C, N4-acetylcytidine; miRNA,
microRNA; rRNA, ribosomal RNA; NAT10, N-acetyltransferase
10; tRNA, transfer RNA.

Figure 5

Uridylation and A-to-I editing. (A)
In the cytoplasm, TUT2, TUT4 and TUT7 are responsible for the
addition of uridylates to pre-miRNAs, fully mature miRNAs and
mRNAs, whereas TUT1 is responsible for the uridylation of snRNAs in
the nucleus. The maturation of miRNAs is regulated by TENT2.
Uridylation is important in the maturation of miRNAs, snRNAs, the
activity of miRNAs, decay. (B) ADAR1 and ADAR2 function as the
'writer' of A-to-I editing for mRNAs, mature miRNAs and pri-miRNAs.
ADAR1/2 affects not only mRNA stability and production, but also
miRNA maturation and function. A-to-I, adenine-to-inosine; TUT,
terminal uridylyl transferase; miRNA, microRNA; snRNA, small
nuclear RNA; ADAR, adenosine deaminase acting on RNA.

Figure 6

Pseudouridylation and U34
modification. Pseudouridylation and U34 modification are important
processes that occur on tRNAs. In mammals, the RNA
pseudouridylation 'writers' primarily include PUS1/3/7/10,
PRUSD2-4, TRUB1/2 and Dyskerin. The catalysis of pseudouridylation
by Dyskerin relies on H/ACA snoRNA. From a functional standpoint,
pseudouridylation contributes to RNA processing, stability and
functionality. The translation of tRNA is markedly affected by
alterations at the U34 position, such as cm5U, τm5U, MCM5U, MCM5s2U
and MCM5Um. MCM5U and its derivatives are formed when ALKBH8
methylates cm5U, which is catalyzed by the ELP1-6 complex. The τm5U
modification in mt-tRNA is catalyzed by GTP binding protein 3 or
mitochondrial translation optimization 1 homolog, whereas SHMT2
provides the starting material for methyl synthesis. PUS,
pseudouridine synthetase; tRNA, transfer RNA; TRUB1/2, TruB
pseudouridine synthase family member 1/2; snoRNA, small nucleolar
RNA; SHMT2, serine hydroxymethyltransferase 2.

Figure 7

When METTL3 is overexpressed in
cardiac fibroblasts, there is a notable increase in the
proliferation of both type I and type III collagen, the activation
of cardiac fibroblasts and the expression of α-SMA. METTL,
methyltransferase-like; α-SMA, α-smooth muscle actin.

Figure 8

The three-axis regulatory model is
shown: (A) Methylation-acetylation synergy, where METTL3-mediated
m6A modifications and NAT10-driven ac4C
modifications co-operatively target the Hippo/YAP and TGF-β/Smad
signaling pathways, exacerbating fibroblast activation and
excessive collagen production. (B) Cell-type-specific programming
revealed by single-cell analysis, as exemplified by
METTL1-catalyzed m7G modifications selectively promoting
fibroblast differentiation into pro-fibrotic phenotypes while
protecting cardiomyocytes. (C) Cross-modification crosstalk,
illustrated by the HuR protein integrating m6A,
uridylation, and A-to-I editing signals to regulate extracellular
matrix dynamics, while the METTL3/FTO balance influences
stress-responsive RNA stability. Collectively, these three axes
drive the pathological phenotype of myocardial fibrosis,
characterized by excessive collagen deposition, increased
ventricular stiffness and diastolic dysfunction. METTL1/3,
methyltransferase-like 1/3; m6A,
N6-methyladenosine; NAT10, N-acetyltransferase
10; YAP, Yes-associated protein; A-to-I, adenine-to-inosine; FTO,
fat mass and obesity-associated.
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Spandidos Publications style
Wu X, Wang R, Chen X and Wang K: Advances in RNA modification in myocardial fibrosis (Review). Int J Mol Med 56: 218, 2025.
APA
Wu, X., Wang, R., Chen, X., & Wang, K. (2025). Advances in RNA modification in myocardial fibrosis (Review). International Journal of Molecular Medicine, 56, 218. https://doi.org/10.3892/ijmm.2025.5659
MLA
Wu, X., Wang, R., Chen, X., Wang, K."Advances in RNA modification in myocardial fibrosis (Review)". International Journal of Molecular Medicine 56.6 (2025): 218.
Chicago
Wu, X., Wang, R., Chen, X., Wang, K."Advances in RNA modification in myocardial fibrosis (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 218. https://doi.org/10.3892/ijmm.2025.5659
Copy and paste a formatted citation
x
Spandidos Publications style
Wu X, Wang R, Chen X and Wang K: Advances in RNA modification in myocardial fibrosis (Review). Int J Mol Med 56: 218, 2025.
APA
Wu, X., Wang, R., Chen, X., & Wang, K. (2025). Advances in RNA modification in myocardial fibrosis (Review). International Journal of Molecular Medicine, 56, 218. https://doi.org/10.3892/ijmm.2025.5659
MLA
Wu, X., Wang, R., Chen, X., Wang, K."Advances in RNA modification in myocardial fibrosis (Review)". International Journal of Molecular Medicine 56.6 (2025): 218.
Chicago
Wu, X., Wang, R., Chen, X., Wang, K."Advances in RNA modification in myocardial fibrosis (Review)". International Journal of Molecular Medicine 56, no. 6 (2025): 218. https://doi.org/10.3892/ijmm.2025.5659
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