The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment
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...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55577-0 |
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| author | Tian Lan Fengwei Gao Yunshi Cai Yinghao Lv Jiang Zhu Hu Liu Sinan Xie Haifeng Wan Haorong He Kunlin Xie Chang Liu Hong Wu |
| author_facet | Tian Lan Fengwei Gao Yunshi Cai Yinghao Lv Jiang Zhu Hu Liu Sinan Xie Haifeng Wan Haorong He Kunlin Xie Chang Liu Hong Wu |
| author_sort | Tian Lan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f28f6ec42e6e43b08f2015ffbef333b5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f28f6ec42e6e43b08f2015ffbef333b52025-01-05T12:37:28ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-024-55577-0The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironmentTian Lan0Fengwei Gao1Yunshi Cai2Yinghao Lv3Jiang Zhu4Hu Liu5Sinan Xie6Haifeng Wan7Haorong He8Kunlin Xie9Chang Liu10Hong Wu11Department of General Surgery, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityLaboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityLaboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityDepartment of Oncology, West China Hospital, Sichuan UniversityDepartment of General Surgery, West China Hospital, Sichuan UniversityAbstract 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.https://doi.org/10.1038/s41467-024-55577-0 |
| spellingShingle | Tian Lan Fengwei Gao Yunshi Cai Yinghao Lv Jiang Zhu Hu Liu Sinan Xie Haifeng Wan Haorong He Kunlin Xie Chang Liu Hong Wu The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment Nature Communications |
| title | The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| title_full | The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| title_fullStr | The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| title_full_unstemmed | The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| title_short | The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| title_sort | protein circpeth 147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment |
| url | https://doi.org/10.1038/s41467-024-55577-0 |
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