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Updated: May 7, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
Published on: October 23, 2018
The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel
Tian Lan1,2,3, Fengwei Gao4,5,6, Yunshi Cai4,5,6
1Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. blue_sky_land@163.com.
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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