IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-66168-y.html
   My bibliography  Save this article

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

Author

Listed:
  • Zhou Lu

    (Fudan University, Institute of Clinical Sciences, Zhongshan Hospital
    Fudan University, Fudan Biotherapy Institute, Zhongshan Hospital
    Fudan University, Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen))

  • Huanchen Shi

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Rongshan Gao

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Chengjie zhong

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Wei Zhang

    (Fudan University, Institute of Clinical Sciences, Zhongshan Hospital)

  • Jian Zhu

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Jianhang Huang

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Ronghua Liu

    (Fudan University, Department of Immunology, School of Basic Medical Sciences
    Fudan University, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences
    Fudan University, Shanghai Fifth People’s Hospital)

  • Yun Xing

    (Fudan University, Department of Immunology, School of Basic Medical Sciences
    Fudan University, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences)

  • Yiwei Chu

    (Fudan University, Department of Immunology, School of Basic Medical Sciences
    Fudan University, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences)

  • Haixiang Sun

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Guoming Shi

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Aiwu Ke

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Jian Zhou

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Jiabin Cai

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Jia Fan

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

  • Pingting Gao

    (Fudan University, Endoscopy Center and Endoscopy Research Institute)

  • Cheng Huang

    (Fudan University, Department of hepatobiliary Surgery and liver Transplantation, Liver Cancer Institute and Zhongshan Hospital)

Abstract

Paraoxonase-1 (PON1) is specifically expressed in the liver and has crucial effects on various liver diseases. The functions and underlying mechanisms of PON1 in hepatocellular carcinoma (HCC) remain unclear. Here, we demonstrate that PON1 serves as a metabolic regulator to counteract regulatory T (Treg) cell-mediated immunosuppression, thereby suppressing HCC progression. Mechanistically, PON1 promotes Von Hippel-Lindau protein (VHL)-mediated ubiquitination and degradation of hypoxia-inducible factor alpha (HIF-1α), leading to attenuated lactic acid production and limited Treg cell accumulation in the HCC microenvironment. In clinical settings, higher PON1 expression is correlated with a better prognosis in patients with HCC. Recombinant PON1 protein (rPON1) effectively impeded tumor growth. Furthermore, enhancing Pon1 expression with quercetin sensitized HCC to anti-programmed death-1(PD-1) therapy in murine HCC. Our findings elucidate a role of PON1 in orchestrating lactic acid production to relieve immunosuppression and suppress HCC, paving the way for targeting PON1 as a therapeutic strategy.

Suggested Citation

  • Zhou Lu & Huanchen Shi & Rongshan Gao & Chengjie zhong & Wei Zhang & Jian Zhu & Jianhang Huang & Ronghua Liu & Yun Xing & Yiwei Chu & Haixiang Sun & Guoming Shi & Aiwu Ke & Jian Zhou & Jiabin Cai & Ji, 2025. "Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66168-y
    DOI: 10.1038/s41467-025-66168-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-66168-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-66168-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66168-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.