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The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment

Author

Listed:
  • Tian Lan

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Fengwei Gao

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Yunshi Cai

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Yinghao Lv

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Jiang Zhu

    (Sichuan University
    Sichuan University)

  • Hu Liu

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Sinan Xie

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Haifeng Wan

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Haorong He

    (Sichuan University)

  • Kunlin Xie

    (Sichuan University
    Sichuan University
    Sichuan University)

  • Chang Liu

    (Sichuan University)

  • Hong Wu

    (Sichuan University
    Sichuan University
    Sichuan University)

Abstract

Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8+ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.

Suggested Citation

  • Tian Lan & Fengwei Gao & Yunshi Cai & Yinghao Lv & Jiang Zhu & Hu Liu & Sinan Xie & Haifeng Wan & Haorong He & Kunlin Xie & Chang Liu & Hong Wu, 2025. "The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55577-0
    DOI: 10.1038/s41467-024-55577-0
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