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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Takayuki Noma,
  • Yuan Li,
  • Yuma Wada,
  • Yuji Morine,
  • Tetsuya Ikemoto,
  • Yu Saito,
  • Mitsuo Shimada,
  • Ajay Goel

摘要

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.