IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43988-4.html
   My bibliography  Save this article

Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion

Author

Listed:
  • Xuemei Gu

    (South China University of Technology)

  • Haoran Wei

    (Southern Medical University)

  • Caixia Suo

    (South China University of Technology)

  • Shengqi Shen

    (Guangdong Academy of Medical Sciences)

  • Chuxu Zhu

    (South China University of Technology)

  • Liang Chen

    (South China University of Technology)

  • Kai Yan

    (Guangdong Academy of Medical Sciences)

  • Zhikun Li

    (South China University of Technology)

  • Zhenhua Bian

    (South China University of Technology)

  • Pinggen Zhang

    (University of Science and Technology of China)

  • Mengqiu Yuan

    (University of Science and Technology of China)

  • Yingxuan Yu

    (South China University of Technology)

  • Jinzhi Du

    (South China University of Technology)

  • Huafeng Zhang

    (University of Science and Technology of China
    Hefei Comprehensive National Science Center)

  • Linchong Sun

    (Southern Medical University)

  • Ping Gao

    (South China University of Technology
    Southern Medical University)

Abstract

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

Suggested Citation

  • Xuemei Gu & Haoran Wei & Caixia Suo & Shengqi Shen & Chuxu Zhu & Liang Chen & Kai Yan & Zhikun Li & Zhenhua Bian & Pinggen Zhang & Mengqiu Yuan & Yingxuan Yu & Jinzhi Du & Huafeng Zhang & Linchong Sun, 2023. "Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43988-4
    DOI: 10.1038/s41467-023-43988-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43988-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-43988-4?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
    ---><---

    References listed on IDEAS

    as
    1. Monika Bambouskova & Laurent Gorvel & Vicky Lampropoulou & Alexey Sergushichev & Ekaterina Loginicheva & Kendall Johnson & Daniel Korenfeld & Mary Elizabeth Mathyer & Hyeryun Kim & Li-Hao Huang & Dust, 2018. "Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis," Nature, Nature, vol. 556(7702), pages 501-504, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Naziia Kurmasheva & Aida Said & Boaz Wong & Priscilla Kinderman & Xiaoying Han & Anna H. F. Rahimic & Alena Kress & Madalina E. Carter-Timofte & Emilia Holm & Demi Horst & Christoph F. Kollmann & Zhen, 2024. "Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways," Nature Communications, Nature, vol. 15(1), pages 1-28, December.

    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:14:y:2023:i:1:d:10.1038_s41467-023-43988-4. 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.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with 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.