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Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation

Author

Listed:
  • Ning Zhang

    (The First Affiliated Hospital of Harbin Medical University)

  • Linmao Sun

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Shuo Zhou

    (Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases
    Sun Yat-sen University Cancer Center)

  • Changyong Ji

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Tianming Cui

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Qi Chu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Jiareng Ye

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Shuhang Liang

    (Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases
    University of Science and Technology of China)

  • Kun Ma

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yufeng Liu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Xianying Li

    (Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases
    Shandong First Medical University)

  • Xinyu Guo

    (The First Affiliated Hospital of Harbin Medical University
    The Fourth Affiliated Hospital of Harbin Medical University
    Ministry of Education)

  • Weizhi Zhang

    (The First Affiliated Hospital of Harbin Medical University
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Xuetian Gu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Cheng Cheng

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Qingrui Zha

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Shengwei Tao

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yunguang Zhang

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Junhui Chu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Chenghui Wu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yuchen Zhang

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Jiabei Wang

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yao Liu

    (University of Science and Technology of China
    Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Lianxin Liu

    (The First Affiliated Hospital of Harbin Medical University)

Abstract

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.

Suggested Citation

  • Ning Zhang & Linmao Sun & Shuo Zhou & Changyong Ji & Tianming Cui & Qi Chu & Jiareng Ye & Shuhang Liang & Kun Ma & Yufeng Liu & Xianying Li & Xinyu Guo & Weizhi Zhang & Xuetian Gu & Cheng Cheng & Qing, 2025. "Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58429-7
    DOI: 10.1038/s41467-025-58429-7
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    References listed on IDEAS

    as
    1. Pradeep Anand Ravindranath & Stefano Forli & David S Goodsell & Arthur J Olson & Michel F Sanner, 2015. "AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility," PLOS Computational Biology, Public Library of Science, vol. 11(12), pages 1-28, December.
    2. Joanna Kaplon & Liang Zheng & Katrin Meissl & Barbara Chaneton & Vitaly A. Selivanov & Gillian Mackay & Sjoerd H. van der Burg & Elizabeth M. E. Verdegaal & Marta Cascante & Tomer Shlomi & Eyal Gottli, 2013. "A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence," Nature, Nature, vol. 498(7452), pages 109-112, June.
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