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The novel 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 a circRNA, circPETH, packaged by extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis of recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in a m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by elevating HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, by virtual and experimental screening, we found that the novel small-molecule Norathyriol was an effective inhibitor that targets the MEG pocket on circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy and boosts cytotoxic CD8+ T-cell function. Our findings determine Norathyriol as a promising anti-HCC agent that contributes to the attenuation of advanced HCC resistance to immune checkpoint blocker (ICB) therapies.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11254 | MetaboLights | 2024-12-09

REPOSITORIES: MetaboLights

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Project description:Background: The objective response rate of anti-programmed death receptor 1 (PD-1) immunotherapy in hepatocellular carcinoma (HCC) remains limited. The tumor immunosuppressive microenvironment mediated by regulatory T cells (Tregs) is a key bottleneck. The traditional Chinese medicine (TCM) compound Fuzheng Jiedu Xiaoji Formula (FZJDXJ) has been proven to improve the clinical efficacy of adjuvant therapy for HCC and remodel the tumor immunosuppressive microenvironment, yet its sensitizing effect and underlying mechanism on PD-1 inhibitors remain unclear.Methods: A total of 55 clinical patients were enrolled, who received either immunotherapy alone or FZJDXJ combined with immunotherapy for 3 cycles. The 1-year efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and peripheral immune responses were analyzed by multicolor flow cytometry. A Hepa1-6 orthotopic HCC mouse model was established and divided into four groups: model group, anti-PD-1 monotherapy group, FZJDXJ monotherapy group, and FZJDXJ combined with anti-PD-1 group. Tumor growth, as well as the function of Tregs and CD8+T cells in the periphery and tumor infiltrates, were assessed. Transcriptomic and metabolomic analyses were conducted to explore the molecular mechanisms and metabolic characteristics of the tumor microenvironment, with in vitro for validation.Results: In the clinical cohort, the 1-year disease control rate (DCR) of the combination therapy group was significantly increased by 28.5% (83.3% vs. 54.8%, p = 0.026), and the incidence of adverse events was reduced by 36.3% (25% vs. 61.3%, p = 0.010) compared with the immunotherapy-alone group. Multicolor flow cytometry confirmed that the combination therapy significantly decreased the proportion of peripheral Tregs and increased the ratio of tissue-resident memory CD8+T cells (TRM) with effector function. In HCC-bearing mice, the combination therapy sensitized the anti-tumor effect of anti-PD-1 treatment, ameliorated immune-related hepatitis and nephritis induced by immunotherapy, enhanced the proportion, cytotoxicity, and proliferation of peripheral and tumor-infiltrating CD8+T cells, and markedly reduced the infiltration and proliferation of Tregs. Multi-omics analyses revealed that the combination therapy significantly downregulated the DHCR7-TFR1 signaling pathway, inhibiting lipotoxicity caused by excessive lipid accumulation in Tregs, which was identified as the central mechanism of the combination therapy for HCC. In vitro confirmed that FZJDXJ containing serum suppressed the activation of the DHCR7-TFR1 signaling pathway, inhibited excessive lipid accumulation in Tregs (detected by BODIPY493/503-FITC, Liperfluo, ROS, and MitoSOX), and attenuated the immunosuppressive capacity of Tregs and their secretion of TGF-βand IL-10 cytokines.Conclusion: FZJDXJ enhances the efficacy of anti-PD-1 therapy for HCC by inhibiting Treg cholesterol metabolic reprogramming and lipotoxicity, thereby relieving the excessive immunosuppression of CD8+T cells by Tregs. This study provides a novel mechanism and clinical evidence for the combination of TCM compounds with immunotherapy for HCC.

			Action	DRS
	3B-siCir-1.wiff	Wiff
	3B-siCir-1.wiff.scan	Wiff
	3B-siCir-2.wiff	Wiff
	3B-siCir-2.wiff.scan	Wiff
	3B-siCir-3.wiff	Wiff

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

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