{
  "abstract": "Background and objective\n\nEndothelial-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\n\nHuman 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\n\nYTHDF1 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\n\nOur 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, Shandong, 250021, China",
    "Key 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"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiaoyu Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinzhi Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Mingquan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Liyuan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Zifang Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiangxi Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Haizhou Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaochun Ma"
    },
    {
      "affs": [
        1
      ],
      "name": "Zongyue Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Shouji Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fe0h58cb4e9er.bib",
  "cited_by": 0,
  "doi": "10.1016/j.athplu.2026.100619",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717901/?tool=EBI",
  "id": "fe0h58cb4e9er",
  "issns": [
    "2667-0909",
    "2667-0895"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13717901",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Full Length Article"
    ],
    [
      "openalex",
      "1312|RNA modifications and cancer"
    ]
  ],
  "openalex": "W7222005180",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717901/pdf/?tool=EBI",
  "pmcid": "PMC13717901",
  "pmid": "42960007",
  "published": "2026-10-15",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/fe0h58cb4e9er.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:38Z",
      "native_id": "PMC:PMC13717901",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13717901"
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    {
      "first_seen": "2026-11-01T00:20:52Z",
      "native_id": "MED:42960007",
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      "url": "https://europepmc.org/article/MED/42960007"
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      "native_id": "PMC13717901",
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      "url": "https://doi.org/10.1016/j.athplu.2026.100619"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA modifications and cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "YTHDF1 aggravates the progression of atherosclerosis by enhancing BRD4 mRNA stability and promoting EndMT transition in an m6A-Dependent manner",
  "title_text": "YTHDF1 aggravates the progression of atherosclerosis by enhancing BRD4 mRNA stability and promoting EndMT transition in an m6A-Dependent manner",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:22:07Z",
  "url": "https://research.draconitic.com/paper/fe0h58cb4e9er",
  "venue": "Atherosclerosis plus",
  "versions": []
}