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Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma

ABSTRACT:

Paraoxonase-1 (PON1) is specifically expressed in the liver and has crucial effects on various liver diseases. The functions and mechanisms underlying of PON1 in hepatocellular carcinoma (HCC) remain obscure. Here, we show that PON1 acts as a metabolic regulator to mitigate regulatory T (Treg) cell-induced immunosuppression and HCC progression. Mechanistically, PON1 crippled lactic acid generation via recruiting Von Hippel-Lindau protein (VHL) to ubiquitinate Hypoxia-inducible factor alpha (HIF-1α), thereby reducing Treg cell frequency in HCC. In clinical settings, high PON1 expression correlated with better prognosis in HCC patients. Recombinant PON1 protein (rPON1) exhibited remarkable potency in impeding tumor growth, meanwhile, enhancing PON1 expression by Quercetin sensitized HCC to anti-programmed death-1 (PD-1) therapy. Our findings elucidate a novel role of PON1 in orchestrating lactic acid production to relieve immunosuppression and suppress HCC, which paves the way for therapeutic intervention of HCC by targeting PON1.

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

PROVIDER: MTBLS12950 | MetaboLights | 2025-09-07

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12950_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12950_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS12950.txt	Txt

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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.

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Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma

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