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

  • Nat Commun. 2025 Jan 2;16(1):333. doi: 10.1038/s41467-024-55577-0.
Tian Lan  #  1  2  3 ,  Fengwei Gao  #  4  5  6 ,  Yunshi Cai  #  4  5  6 ,  Yinghao Lv  4  5  6 ,  Jiang Zhu  6  7 ,  Hu Liu  4  5  6 ,  Sinan Xie  4  5  6 ,  Haifeng Wan  4  5  6 ,  Haorong He  6 ,  Kunlin Xie  4  5  6 ,  Chang Liu  8 ,  Hong Wu  9  10  11
Affiliations
  • 1. Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 2. Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 3. Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 4. Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 5. Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China.
  • 6. Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
  • 7. Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 8. Department of Oncology, West China Hospital, Sichuan University, Chengdu, China.
  • 9. Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 10. Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 11. Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • # Contributed equally.
PMID: 39747873 DOI: 10.1038/s41467-024-55577-0
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.

Products