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Peer-reviewedCC BYnpj Precision Oncology

GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in hepatocellular carcinoma

  • Takayuki Noma1
  • Yuan Li1
  • Yuma Wada2
  • Yuji Morine2
  • Tetsuya Ikemoto2
  • Yu Saito2
  • Mitsuo Shimada2
  • Ajay Goel1
  1. 1Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia
  2. 2Department of Surgery, Tokushima University
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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.

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Cite

BibTeXRIS
BibTeX
@article{noma2026glp1,
  title = {{GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in hepatocellular carcinoma}},
  author = {Takayuki Noma and Yuan Li and Yuma Wada and Yuji Morine and Tetsuya Ikemoto and Yu Saito and Mitsuo Shimada and Ajay Goel},
  journal = {npj Precision Oncology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41698-026-01584-x},
  url = {https://doi.org/10.1038/s41698-026-01584-x},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in hepatocellular carcinoma
AU  - Takayuki Noma
AU  - Yuan Li
AU  - Yuma Wada
AU  - Yuji Morine
AU  - Tetsuya Ikemoto
AU  - Yu Saito
AU  - Mitsuo Shimada
AU  - Ajay Goel
PY  - 2026
DA  - 2026/06/01
JO  - npj Precision Oncology
DO  - 10.1038/s41698-026-01584-x
UR  - https://doi.org/10.1038/s41698-026-01584-x
AB  - 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.
SN  - 2397-768X
ER  -