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Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review)

  • Authors:
    • Ying Zhu
    • Zhixin Hu
    • Jianshuo Liu
    • Huaqing Duan
    • Jiqiang Zeng
    • Xiaosheng Li
    • Yang Tang
    • Ziling Song
    • Zhipeng Wu
    • Shanrong Zhang
    • Yuxuan Zhang
    • Fang Qiu
    • Chen Lu
  • View Affiliations / Copyright

    Affiliations: Department of Blood Transfusion, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, First Clinical Medical College of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, School of Medical Technology, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, School of Nursing, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 180
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    Published online on: September 1, 2025
       https://doi.org/10.3892/ijmm.2025.5621
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Abstract

Atherosclerosis is a chronic and progressive vascular disease involving the gradual accumulation of lipids, cholesterol, cellular debris, and fibrous elements within the arterial wall. This process leads to the thickening and hardening of arteries, resulting in restricted blood flow and reduced oxygen delivery to tissues. Over time, these pathological changes significantly elevate the risk of life‑threatening cardiovascular events, including myocardial infarction and ischemic stroke. Recent studies emphasize the significant role of epigenetic modifications and non‑coding RNAs (ncRNAs) in regulating the progression of atherosclerosis. Histone modifications, DNA methylation, and ncRNAs interact to modulate gene expression, influencing endothelial dysfunction, lipid metabolism, and inflammatory processes. Epigenetic regulators, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), control key vascular genes, while ncRNAs like microRNAs (miRNAs), long non‑coding RNAs (LncRNAs), and circular RNAs (circRNAs) contribute to the modulation of cholesterol efflux and foam cell formation. Understanding the complex interplay between these molecular pathways offers new therapeutic insights for managing atherosclerosis and its complications. The reversible nature of epigenetic changes, alongside ncRNA‑based therapies, holds promising potential for future clinical applications, though challenges such as delivery mechanisms and specificity remain. 
View Figures

Figure 1

Stages and cellular events in the
onset and progression of atherosclerosis. Lipoproteins infiltrate
the intimal layer at regions subjected to disturbed shear stress.
Within the intima, these lipoproteins undergo aggregation,
oxidation, and other modifications, leading to the activation of
overlying endothelial cells. In response, ECs upregulate adhesion
and chemotactic molecules, promoting monocyte recruitment.
Infiltrating monocytes differentiate into macrophages and engulf
modified lipoproteins, giving rise to lipid-rich foam cells.
Although less numerous than monocytes, T-lymphocytes also migrate
into the intima, where they modulate the activity of the immune
cells, VSMCs, and endothelial cells. In response to signals
released by activated leukocytes, SMCs from the tunica media can
migrate into the intimal layer. In response to signaling molecules
secreted by activated leukocytes, SMCs originating from the tunica
media are capable of migrating into the intimal layer. This
migration is believed to be driven by platelet-derived growth
factor (PDGF), a potent chemoattractant for SMCs, which is released
by macrophages and accumulated by activated platelets at sites of
endothelial injury or intraplaque hemorrhage. LDL, low-density
lipoprotein; oxLDL, oxidized LDL; ROS, reactive oxygen species;
NF-κB, nuclear factor kappa-light-chain-enhancer of activated B
cells; NO, nitric oxide; ICAM-1, intercellular adhesion molecule 1;
VCAM-1, vascular cell adhesion molecule 1; MCP-1, monocyte
chemoattractant protein 1; MPO, myeloperoxidase; CCR2, C-C
chemokine receptor type 2; TNF-α, tumor necrosis factor alpha;
IL-1β, interleukin 1 beta; IL-6, interleukin 6.

Figure 2

Mechanisms of cellular turnover in
atherosclerotic plaque development. As atherosclerotic plaques
develop, both resident and newly recruited SMCs contribute to
intimal thickening by producing extracellular matrix components,
such as collagen, elastin, proteoglycans, and glycosaminoglycans.
However, T cell-derived cytokines, particularly interferon-gamma
(IFNγ), can disrupt this process by inhibiting SMC-mediated
synthesis of interstitial collagen, thereby compromising the
integrity and reparative capacity of the fibrous cap.
Simultaneously, activated macrophages secrete elevated levels of
matrix metalloproteinases (MMPs), a family of enzymes that break
down interstitial collagen, further weakening the fibrous cap and
making the plaque more prone to rupture. Within the evolving
lesion, both SMCs and macrophages retain the capacity to
proliferate, and evidence suggests that these cell types can
undergo phenotypic switching, or metaplasia, enabling them to adopt
alternate cellular identities. As the plaque matures, these cells
may also undergo programmed cell death, such as apoptosis, and the
remnants of dead or dying cells accumulate to form the lipid-rich
necrotic core of the atheroma. This accumulation is exacerbated by
defective efferocytosis, the process responsible for clearing
apoptotic cells. LDL also contributes to lesion progression through
its role in lipid deposition and inflammation. LDL, low-density
lipoprotein; oxLDL, oxidized LDL; ROS, reactive oxygen species;
TNF-α, tumor necrosis factor alpha; IL-1β, interleukin 1 beta;
IFN-γ, interferon gamma; MCP-1, monocyte chemoattractant protein 1;
MMP, matrix metalloproteinase; PDGF, platelet-derived growth
factor; CD36, cluster of differentiation 36; SR-A, scavenger
receptor class A; SMC, smooth muscle cell.

Figure 3

Mechanistic pathway linking
ox-ldl-induced chromatin remodeling, DNA methylation, and ncRNA
regulation in atherosclerotic plaque progression. ox-LDL induces
DNMT3B expression, leading to DNA methylation at CpG sites of key
atheroprotective genes (CREG, KLF2, ABCA1). Methylated DNA is
identified by methyl-CpG-binding proteins (MeCP2/MBDs), which
recruit HDACs. Additionally, miR-33 promotes the recruitment of the
PRC2 complex, leading to the deposition of H3K27me3, which causes
chromatin condensation and transcriptional silencing. oxLDL,
oxidized low-density lipoprotein; miR, microRNA; DNMT1, DNA
methyltransferase 1; ABCA1, ATP-binding cassette transporter A1;
CpG, cytosine-phosphate-guanine; MeCP2, methyl-CpG-binding protein
2; MBD, methyl-CpG-binding domain; HDAC, histone deacetylase; PRC2,
polycomb repressive complex 2; EZH2, enhancer of zeste homolog 2;
AC-JARID2, acetylated Jumonji and AT-rich interaction
domain-containing 2; H3K27me3, trimethylation of lysine 27 on
histone H3; CREG, cellular repressor of E1A-stimulated genes; NO,
nitric oxide; KLF2, Krüppel-like factor 2.

Figure 4

Non-coding RNA and epigenetic
crosstalk in atherosclerosis progression. miR-33a targets ABCA1 by
recruiting PRC2, leading to H3K27me3 deposition and repression of
ABCA1 expression. DNMT3B methylates the ABCA1 promoter, further
silencing it. TET1/2/3 enzymes can reverse this methylation. This
regulation results in reduced cholesterol efflux, contributing to
foam cell accumulation and plaque instability. In the other hand,
miR-145 modulates VSMC growth, promoting plaque stability by
increasing collagen and fibrous cap area, while miR-155 and
miR-125a-5p regulate lipid uptake and inflammation in macrophages.
lncRNA MeXis counteracts PRC2, facilitating ABCA1 transcription and
cholesterol efflux, reducing foam cell formation and plaque
instability. 5-aza-dC, 5-aza-2′-deoxycytidine; DNMT, DNA
methyltransferase; lncRNA, long non-coding RNA; MeXis,
macrophage-expressed LXR-induced sequence; ABCA1, ATP-binding
cassette transporter A1; miR, microRNA; PRC2, polycomb repressive
complex 2; EZH2, enhancer of zeste homolog 2; H3K27me3,
trimethylation of histone H3 at lysine 27; VSMC, vascular smooth
muscle cell.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu Y, Hu Z, Liu J, Duan H, Zeng J, Li X, Tang Y, Song Z, Wu Z, Zhang S, Zhang S, et al: Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review). Int J Mol Med 56: 180, 2025.
APA
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X. ... Lu, C. (2025). Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review). International Journal of Molecular Medicine, 56, 180. https://doi.org/10.3892/ijmm.2025.5621
MLA
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X., Tang, Y., Song, Z., Wu, Z., Zhang, S., Zhang, Y., Qiu, F., Lu, C."Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review)". International Journal of Molecular Medicine 56.5 (2025): 180.
Chicago
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X., Tang, Y., Song, Z., Wu, Z., Zhang, S., Zhang, Y., Qiu, F., Lu, C."Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 180. https://doi.org/10.3892/ijmm.2025.5621
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu Y, Hu Z, Liu J, Duan H, Zeng J, Li X, Tang Y, Song Z, Wu Z, Zhang S, Zhang S, et al: Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review). Int J Mol Med 56: 180, 2025.
APA
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X. ... Lu, C. (2025). Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review). International Journal of Molecular Medicine, 56, 180. https://doi.org/10.3892/ijmm.2025.5621
MLA
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X., Tang, Y., Song, Z., Wu, Z., Zhang, S., Zhang, Y., Qiu, F., Lu, C."Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review)". International Journal of Molecular Medicine 56.5 (2025): 180.
Chicago
Zhu, Y., Hu, Z., Liu, J., Duan, H., Zeng, J., Li, X., Tang, Y., Song, Z., Wu, Z., Zhang, S., Zhang, Y., Qiu, F., Lu, C."Epigenetic‑ncRNA crosstalk in atherosclerosis: Mechanisms, disease progression and therapeutic potential (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 180. https://doi.org/10.3892/ijmm.2025.5621
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