{
  "abstract": "Nonalcoholic fatty liver disease (NAFLD) is emerging as the leading cause of chronic liver disease, posing a global public health challenge without available therapeutic approaches. Protein arginine methyltransferase 6 is a type I PRMT that asymmetrically dimethylates arginine residues of a variety of substrates implicated in many diseases. However, its role in NAFLD pathologies has not been clarified. In this study, we show that PRMT6 is upregulated in NAFLD and NASH of mice and human patients. Prmt6-deficient mice are protected from diet-induced hepatic steatosis, steatohepatitis, insulin resistance, and glucose tolerance. Mechanistically, PRMT6 interacts with and dimethylates Forkhead box K1 (FOXK1) at four conserved arginine residues (R161, R191, R259, and R486), maintaining its nuclear localization and transcriptional activity as a repressor/activator, inhibiting fatty acid oxidation and stimulating lipogenesis programs, respectively. PRMT6 competes with glycogen synthase kinase-3 (GSK3) for binding to FOXK1 and triggers FOXK1 methylation. This methylation prevents FOXK1 from GSK3-mediated phosphorylation, leading to its dissociation from 14-3-3, enhanced nuclear retention, and transcriptional activity. Conversely, the methylation-defective FOXK1 mutant (4RK) has the opposite effect and confers resistance to diet-induced hepatic steatosis in mice. Moreover, pharmacological inhibition of PRMT6 by EPZ020411 ameliorates NAFLD progression in mice. Thus, our study demonstrates the PRMT6-FOXK1 axis as a critical regulator of NAFLD and that targeting PRMT6 represents a novel therapeutic intervention for NAFLD.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Targeted Therapy and Precision Medicine, Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.",
    "Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.",
    "Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.",
    "Department of Pathology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200335, China.",
    "Department of Bariatric and Metabolic Surgery, Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yang Sun"
    },
    {
      "affs": [
        1
      ],
      "name": "Tao Chen"
    },
    {
      "affs": [
        2
      ],
      "name": "Lei Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Jinlin Duan"
    },
    {
      "affs": [
        0
      ],
      "name": "Junyan Xue"
    },
    {
      "affs": [
        3
      ],
      "name": "Wentao Huang"
    },
    {
      "affs": [
        4
      ],
      "name": "Jianzhong Di"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Yonglong Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/akw1tzj3x5qsy.bib",
  "cited_by": 0,
  "doi": "10.1016/j.apsb.2026.08.003",
  "fulltext_url": "https://europepmc.org/articles/PMC13712363",
  "id": "akw1tzj3x5qsy",
  "issns": [
    "2211-3835",
    "2211-3843"
  ],
  "landing_url": "https://europepmc.org/article/MED/42948769",
  "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",
      "Original Article"
    ],
    [
      "openalex",
      "2713|Liver Disease Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7196924369",
  "pdf_url": "https://europepmc.org/articles/PMC13712363?pdf=render",
  "pmcid": "PMC13712363",
  "pmid": "42948769",
  "published": "2026-08-06",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/akw1tzj3x5qsy.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:36Z",
      "native_id": "MED:42948769",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42948769"
    },
    {
      "first_seen": "2026-10-31T12:22:57Z",
      "native_id": "PMC13712363",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.apsb.2026.08.003"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Liver Disease Diagnosis and Treatment",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice.",
  "title_text": "Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:57Z",
  "url": "https://research.draconitic.com/paper/akw1tzj3x5qsy",
  "venue": "Acta pharmaceutica Sinica. B",
  "versions": []
}