YTHDF1 aggravates the progression of atherosclerosis by enhancing BRD4 mRNA stability and promoting EndMT transition in an m6A-Dependent manner
- 1Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, Shandong, 250021, China
- 2Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
Abstract
Background and objective
Endothelial-to-mesenchymal transition (EndMT) is a crucial process driving vascular remodeling in atherosclerosis (AS). N6-methyladenosine (m6A) RNA methylation, regulated by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), an m6A reader that modulates RNA stability and translation, influences various cellular functions, but its specific role in AS-related EndMT remains unclear. This study aimed to investigate the role of the m6A reader YTHDF1 in AS progression, focusing on its regulation of bromodomain containing 4 (BRD4), a central epigenetic regulator in the Bromodomain and Extra-Terminal (BET) family, and subsequent promotion of EndMT.Methods
Human AS datasets (involving 6 clinical samples in GSE97210 and 104 clinical samples in GSE100927) and single-cell RNA sequencing data from Apoe-/- mice (n = 3 in total) were analyzed to assess YTHDF1 expression and correlation. YTHDF1-/-Apoe-/- mice (n = 5) were generated and fed a high-fat diet to evaluate plaque formation. In vitro, human umbilical vein endothelial cells (HUVECs) were used for gain/loss-of-function experiments. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), site-directed mutagenesis, and functional assays (Transwell, wound healing) were employed to elucidate the molecular mechanism.Results
YTHDF1 was significantly upregulated in human AS plaques (P < 0.001) and positively correlated with EndMT markers. ScRNA-seq analysis revealed a progressive increase in YTHDF1-expressing endothelial cells during plaque progression in Apoe-/- mice. YTHDF1 knockout in Apoe-/- mice markedly reduced atherosclerotic lesion area (P = 0.0023), lipid deposition (P = 0.0007), and en face plaque area (P = 0.0038), accompanied by attenuated EndMT. In HUVECs, YTHDF1 overexpression promoted EndMT, enhanced cell migration (P < 0.01), and upregulated BRD4 (1.53 ± 0.20vs.1 ± 0.19 in control, p = 0.027). Mechanistically, METTL3-mediated m6A modification at a specific site in the 5'-UTR of BRD4 mRNA was recognized by YTHDF1, which stabilized BRD4 transcripts and increased BRD4 protein levels. Conversely, BRD4 knockdown suppressed the EndMT phenotype and impaired HUVEC migration (P < 0.01).Conclusion
Our findings uncover a novel pathogenic axis in AS where YTHDF1, by recognizing METTL3-mediated m6A modification on BRD4 mRNA, enhances its stability. This leads to increased BRD4 expression, which in turn drives EndMT and exacerbates disease progression. The YTHDF1-m6A-BRD4 pathway may represent a potential therapeutic target for AS which requires further preclinical validation.
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BibTeX
@article{zhou2026ythdf1,
title = {{YTHDF1 aggravates the progression of atherosclerosis by enhancing BRD4 mRNA stability and promoting EndMT transition in an m6A-Dependent manner}},
author = {Xiaoyu Zhou and Xinzhi Liu and Mingquan Wang and Liyuan Wang and Zifang Xiao and Xiangxi Zhang and Jun Sun and Haizhou Zhang and Xiaochun Ma and Zongyue Li and Shouji Zhang},
journal = {Atherosclerosis plus},
year = {2026},
month = oct,
doi = {10.1016/j.athplu.2026.100619},
url = {https://europepmc.org/article/PMC/PMC13717901},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - YTHDF1 aggravates the progression of atherosclerosis by enhancing BRD4 mRNA stability and promoting EndMT transition in an m6A-Dependent manner
AU - Xiaoyu Zhou
AU - Xinzhi Liu
AU - Mingquan Wang
AU - Liyuan Wang
AU - Zifang Xiao
AU - Xiangxi Zhang
AU - Jun Sun
AU - Haizhou Zhang
AU - Xiaochun Ma
AU - Zongyue Li
AU - Shouji Zhang
PY - 2026
DA - 2026/10/15
JO - Atherosclerosis plus
DO - 10.1016/j.athplu.2026.100619
UR - https://europepmc.org/article/PMC/PMC13717901
AB - Background and objective Endothelial-to-mesenchymal transition (EndMT) is a crucial process driving vascular remodeling in atherosclerosis (AS). N6-methyladenosine (m6A) RNA methylation, regulated by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), an m6A reader that modulates RNA stability and translation, influences various cellular functions, but its specific role in AS-related EndMT remains unclear. This study aimed to investigate the role of the m6A reader YTHDF1 in AS progression, focusing on its regulation of bromodomain containing 4 (BRD4), a central epigenetic regulator in the Bromodomain and Extra-Terminal (BET) family, and subsequent promotion of EndMT.Methods Human AS datasets (involving 6 clinical samples in GSE97210 and 104 clinical samples in GSE100927) and single-cell RNA sequencing data from Apoe-/- mice (n = 3 in total) were analyzed to assess YTHDF1 expression and correlation. YTHDF1-/-Apoe-/- mice (n = 5) were generated and fed a high-fat diet to evaluate plaque formation. In vitro, human umbilical vein endothelial cells (HUVECs) were used for gain/loss-of-function experiments. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), site-directed mutagenesis, and functional assays (Transwell, wound healing) were employed to elucidate the molecular mechanism.Results YTHDF1 was significantly upregulated in human AS plaques (P < 0.001) and positively correlated with EndMT markers. ScRNA-seq analysis revealed a progressive increase in YTHDF1-expressing endothelial cells during plaque progression in Apoe-/- mice. YTHDF1 knockout in Apoe-/- mice markedly reduced atherosclerotic lesion area (P = 0.0023), lipid deposition (P = 0.0007), and en face plaque area (P = 0.0038), accompanied by attenuated EndMT. In HUVECs, YTHDF1 overexpression promoted EndMT, enhanced cell migration (P < 0.01), and upregulated BRD4 (1.53 ± 0.20vs.1 ± 0.19 in control, p = 0.027). Mechanistically, METTL3-mediated m6A modification at a specific site in the 5'-UTR of BRD4 mRNA was recognized by YTHDF1, which stabilized BRD4 transcripts and increased BRD4 protein levels. Conversely, BRD4 knockdown suppressed the EndMT phenotype and impaired HUVEC migration (P < 0.01).Conclusion Our findings uncover a novel pathogenic axis in AS where YTHDF1, by recognizing METTL3-mediated m6A modification on BRD4 mRNA, enhances its stability. This leads to increased BRD4 expression, which in turn drives EndMT and exacerbates disease progression. The YTHDF1-m6A-BRD4 pathway may represent a potential therapeutic target for AS which requires further preclinical validation.
SN - 2667-0909
SN - 2667-0895
ER -