{
  "abstract": "Pathological cardiac hypertrophy, a major risk factor for heart failure, is regulated by complex transcriptional networks. We previously identified the transcription factor ZBED6 as a key regulator for skeletal muscle hypertrophy, its role in the cardiac hypertrophy remains unexplored. Here, we report that ZBED6 is a key suppressor of pathological cardiac hypertrophy. ZBED6 is markedly reduced in myocardial tissues from patients with cardiac hypertrophy. ZBED6-deficient pigs exhibited cardiac hypertrophy with diastolic dysfunction. Integrative transcriptomic and ChIP-seq analyses identified MEOX1 as a direct negative target of ZBED6. Loss of ZBED6 upregulates MEOX1 transcription, which subsequently activated ERK1/2 signaling, leading to impaired autophagy-induced hypertrophy. Knockdown of MEOX1 reduced ERK1/2 phosphorylation and mitigated cardiomyocyte hypertrophy induced by ZBED6 deficiency. Similarly, pharmacological inhibition of ERK1/2 restored autophagy and alleviated hypertrophy in ZBED6-depleted cardiomyocytes. Collectively, these findings define a previously unrecognized ZBED6–MEOX1–ERK1/2 axis that critically regulates cardiac hypertrophy and represents a potential therapeutic target. Author summary: An enlarged heart may initially help the body cope with stress, but persistent enlargement can impair heart function and increase the risk of heart failure. We investigated whether a gene regulator called ZBED6 helps protect the heart from this harmful growth. We found that ZBED6 levels were reduced in heart tissue from people with cardiac hypertrophy. Pigs lacking ZBED6 developed enlarged hearts, thicker heart walls, enlarged heart muscle cells, and impaired relaxation, while their pumping ability remained largely preserved. Using pig and human heart cells, we found that loss of ZBED6 increased the activity of another gene, MEOX1. This change disrupted the cellular recycling process that removes damaged or unnecessary material. Reducing MEOX1 activity or blocking the downstream signal restored cellular recycling and limited heart-cell enlargement. Our findings identify ZBED6 as an important brake on harmful heart growth and reveal a previously unknown link between gene regulation, cellular recycling, and cardiac hypertrophy. This work may guide future studies seeking new approaches to prevent or treat pathological heart enlargement.",
  "abstract_shown": true,
  "affiliations": [
    "Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China",
    "Ultrasound in Cardiac Electrophysiology and Biomechanics Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China",
    "Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China",
    "Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
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        0
      ],
      "name": "Xiao Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaopeng Liu"
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    {
      "affs": [
        2
      ],
      "name": "Ruirui Pan"
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    {
      "affs": [
        3
      ],
      "name": "Huan Liu"
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    {
      "name": "Junying Xiao"
    },
    {
      "name": "Xiangkai Leng"
    },
    {
      "name": "Hongmei Zhang"
    },
    {
      "name": "Dengke Pan"
    },
    {
      "name": "Shengzhong Duan"
    },
    {
      "name": "Jiangwei Wu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0byc2sdxvzfh5.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012329",
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  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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  "native_subjects": [
    [
      "openalex",
      "2705|Cardiac Fibrosis and Remodeling"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Biological tissue/Muscle tissue/Muscle cells/Cardiomyocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Cardiovascular anatomy/Heart"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Autophagic cell death"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Muscle cells/Cardiomyocytes"
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      "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/MAPK signaling cascades"
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    [
      "plos",
      "/Medicine and health sciences/Anatomy/Cardiovascular anatomy/Heart"
    ],
    [
      "plos",
      "/Medicine and health sciences/Cardiology/Cardiac hypertrophy"
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      "plos",
      "/Research and analysis methods/Immunologic techniques/Immunoassays/Immunofluorescence"
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  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012329&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-08",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/0byc2sdxvzfh5.ris",
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    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pgen.1012329",
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      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012329"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
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    {
      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
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  "title": "ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1–ERK1/2–dependent autophagy dysfunction",
  "title_text": "ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1–ERK1/2–dependent autophagy dysfunction",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:30Z",
  "url": "https://research.draconitic.com/paper/0byc2sdxvzfh5",
  "venue": "PLOS Genetics",
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}