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Nature Communications

Nature Communications

IF: 14.7
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The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment

Published:2 January 2025 DOI: 10.1038/s41467-024-55577-0 PMID: 39747873
Tian Lan,?Fengwei Gao,?Yunshi Cai,?Yinghao Lv,?Jiang Zhu,?Hu Liu,?Sinan Xie,?Haifeng Wan,?Haorong He,?Kunlin Xie,?Chang Liu,?Hong Wu

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 237 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 237 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 237 suppliers $23.00-$2200.00
5(6)-(N-SUCCINIMIDYLOXYCARBONYL)-3',6',O,O'-DIACETYLFLUORESCEIN 150347-59-4 C29H19NO11 237 suppliers $23.00-$2200.00

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