2. Academic Validation
  3. The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment

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

Affiliations

  • 1 Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. blue_sky_land@163.com.
  • 2 Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China. blue_sky_land@163.com.
  • 3 Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. blue_sky_land@163.com.
  • 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. wuhong@scu.edu.cn.
  • 10 Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China. wuhong@scu.edu.cn.
  • 11 Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. wuhong@scu.edu.cn.
  • # 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.

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