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

作者：Tian Lan, Fengwei Gao, Yunshi Cai, Yinghao Lv, Jiang Zhu, Hu Liu, Sinan Xie, Haifeng Wan, Haorong He, Kunlin Xie, Chang Liu, Hong Wu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-024-55577-0 · 被引用次数：70 · 研究领域：Circular RNAs in diseases、RNA modifications and cancer、MicroRNA in disease regulation

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. Tumor-associated macrophages (TAMs) are associated with poor prognosis and low responses to immunotherapy. Here, authors discover that a circular RNA, circPETH, produced by TAMs generates a metabolic reprogramming in hepatocellular carcinoma that promotes metastasis and...