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Review Open Access

Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review)

  • Authors:
    • Jinshun Li
    • Weiyun Liu
    • Jin Yang
    • Yanan Li
  • View Affiliations / Copyright

    Affiliations: Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu 730900, P.R. China, Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu 730900, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 212
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    Published online on: May 29, 2026
       https://doi.org/10.3892/mmr.2026.13922
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Abstract

Cutaneous fibrosis is sustained by epigenetic ‘memory’ rather than chronic inflammation. DNA hypermethylation, repressive histone marks and non‑coding RNA networks lock dermal fibroblasts into a collagen‑secretory state that can persist years after wounding. Single‑cell methylomes have identified DNA methyltransferase (DNMT)3B as the key epigenetic writer driving anti‑fibrotic gene silencing, whereas N6‑methyladenosine‑modified long non‑coding RNAs and reinforce these loops by tethering methylation machinery to chromatin. Local delivery of DNMT inhibitors, microRNA‑29 mimics or antisense oligonucleotides via dissolvable microneedles, metal‑organic framework patches or exosome arrays reproducibly reduces scar volume by 25‑55% in pre‑clinical models without systemic exposure of therapeutic agents. The present review integrates multi‑omic mechanistic data with emerging device platforms to chart a precision roadmap for converting scar‑forming repair into scar‑sparing regeneration.
View Figures

Figure 1

Comprehensive epigenetic toolbox used
in pathological scar research. Schematic overview of advanced
epigenomic platforms, including EPIC/450K arrays, single-cell
MBD-seq, single-cell ATAC-seq and spatial-ATAC-seq, and CRISPR-dCas
editing systems used to map DNA methylation, histone marks, RNA m6A
methylation and chromatin accessibility in cutaneous fibrosis. The
figure highlights the progression from bulk-tissue profiling to
single-cell and spatial resolution. Collectively, the integration
of these multi-omic platforms facilitates the transition from
correlative bulk-tissue profiling to the identification of causal,
cell-type-specific epigenetic drivers, thereby pinpointing precise
therapeutic targets within the scar microenvironment. Created with
Figdraw. MBD-seq, methyl-CpG binding domain sequencing; miR,
microRNA; pri-miR, primary microRNA; DMC, differentially methylated
CpG site; dCas, dead Cas; TET1, Tet methylcytosine dioxygenase 1;
METTL, methyltransferase-like; m6A, N6-methyladenosine; ATAC-seq,
assay for transposase-accessible chromatin with high-throughput
sequencing; PTEN, phosphatase and tensin homolog; RASAL1, RAS
protein activator-like 1; COL1A1, type I collagen α1 chain; α-SMA,
α-smooth muscle actin.

Figure 2

Histone-code circuitry drives
pro-fibrotic memory in scar fibroblasts. The figure illustrates the
following key histone modification mechanisms: i)
HDAC4/5-MEF2A-mediated Smad7 silencing; ii) EZH2/H3K27me3
signaling-mediated repression of anti-fibrotic loci; and iii)
BET/BRD4 recruitment of transcriptional machinery to collagen
promoters. These histone modifiers are all subject to lncRNA-guided
modulation. Thus, the convergence of histone deacetylation,
repressive methylation and bromodomain-mediated epigenetic reading
establishes a repressive chromatin environment that silences
negative regulators of TGF-β signaling, effectively locking
fibroblasts into a persistent, self-reinforcing pro-fibrotic state.
Created with Figdraw. HDAC, histone deacetylase; EZH2, enhancer of
zeste homolog 2; SIRT1, sirtuin 1; MEF2A, myocyte-specific enhancer
factor 2A; SMAD, small mothers against decapentaplegic; H3K27me3,
histone H3 lysine 27 trimethylation; BET, bromodomain and
extra-terminal; BRD, bromodomain-containing protein; lncRNA, long
non-coding RNA.
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Copy and paste a formatted citation
Spandidos Publications style
Li J, Liu W, Yang J and Li Y: Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review). Mol Med Rep 34: 212, 2026.
APA
Li, J., Liu, W., Yang, J., & Li, Y. (2026). Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review). Molecular Medicine Reports, 34, 212. https://doi.org/10.3892/mmr.2026.13922
MLA
Li, J., Liu, W., Yang, J., Li, Y."Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review)". Molecular Medicine Reports 34.1 (2026): 212.
Chicago
Li, J., Liu, W., Yang, J., Li, Y."Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review)". Molecular Medicine Reports 34, no. 1 (2026): 212. https://doi.org/10.3892/mmr.2026.13922
Copy and paste a formatted citation
x
Spandidos Publications style
Li J, Liu W, Yang J and Li Y: Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review). Mol Med Rep 34: 212, 2026.
APA
Li, J., Liu, W., Yang, J., & Li, Y. (2026). Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review). Molecular Medicine Reports, 34, 212. https://doi.org/10.3892/mmr.2026.13922
MLA
Li, J., Liu, W., Yang, J., Li, Y."Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review)". Molecular Medicine Reports 34.1 (2026): 212.
Chicago
Li, J., Liu, W., Yang, J., Li, Y."Epigenetic orchestration of scar formation: Therapeutic potential of targeting DNA methylation and non‑coding RNAs in cutaneous fibrosis (Review)". Molecular Medicine Reports 34, no. 1 (2026): 212. https://doi.org/10.3892/mmr.2026.13922
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