{
  "abstract": "Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes and obesity, have recently attracted attention for potential anti-tumor effects, although their mechanisms remain unclear. Given their role in metabolic regulation, we hypothesized that GLP-1RAs may target cancer-specific metabolic vulnerabilities. Hepatocellular carcinoma (HCC) is characterized by metabolic reprogramming and enhanced glycolysis, which contribute to therapeutic resistance. Here, we investigated the anti-tumor effects of a GLP-1RA in HCC, focusing on its ability to modulate glycolytic pathways and enhance sensitivity to Lenvatinib. Lenvatinib-resistant HCC cells exhibited suppressed AMPKα1 and increased HIF-1α and PFKFB3 expression, promoting glycolytic adaptation. GLP-1RA treatment restored AMPKα1 activity while suppressing HIF-1α/PFKFB3 signaling, thereby reducing glycolytic activity and enhancing apoptosis. Combination treatment with GLP-1RA and Lenvatinib significantly inhibited tumor cell growth in resistant models. These findings suggest that the AMPKα1/HIF-1α/PFKFB3 axis represents a metabolic vulnerability in Lenvatinib-resistant HCC and support GLP-1RA-based combination strategies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia",
    "Department of Surgery, Tokushima University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Takayuki Noma"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuan Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuma Wada"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuji Morine"
    },
    {
      "affs": [
        1
      ],
      "name": "Tetsuya Ikemoto"
    },
    {
      "affs": [
        1
      ],
      "name": "Yu Saito"
    },
    {
      "affs": [
        1
      ],
      "name": "Mitsuo Shimada"
    },
    {
      "affs": [
        0
      ],
      "name": "Ajay Goel"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/47jyma3dyz6ps.bib",
  "cited_by": 0,
  "doi": "10.1038/s41698-026-01584-x",
  "fulltext_url": "https://doi.org/10.1038/s41698-026-01584-x",
  "id": "47jyma3dyz6ps",
  "issns": [
    "2397-768X"
  ],
  "landing_url": "https://doi.org/10.1038/s41698-026-01584-x",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC254-282"
    ],
    [
      "openalex",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
  ],
  "openalex": "W7166513968",
  "pdf_url": "https://www.nature.com/articles/s41698-026-01584-x_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/47jyma3dyz6ps.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:45:36Z",
      "native_id": "96cdef2b344f4ea2aabdee7cb7fcb975",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41698-026-01584-x"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Hypoxia, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in hepatocellular carcinoma",
  "title_text": "GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in hepatocellular carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:36Z",
  "url": "https://research.draconitic.com/paper/47jyma3dyz6ps",
  "venue": "npj Precision Oncology",
  "versions": []
}