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

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, Qingrui Zha, Shengwei Tao, Yunguang Zhang, Junhui Chu, Chenghui Wu, Yuchen Zhang, Jiabei Wang (), Yao Liu () and Lianxin Liu ()
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Ning Zhang: The First Affiliated Hospital of Harbin Medical University
Linmao Sun: University of Science and Technology of China
Shuo Zhou: Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
Changyong Ji: University of Science and Technology of China
Tianming Cui: University of Science and Technology of China
Qi Chu: University of Science and Technology of China
Jiareng Ye: University of Science and Technology of China
Shuhang Liang: Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
Kun Ma: University of Science and Technology of China
Yufeng Liu: University of Science and Technology of China
Xianying Li: Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery
Xinyu Guo: The First Affiliated Hospital of Harbin Medical University
Weizhi Zhang: The First Affiliated Hospital of Harbin Medical University
Xuetian Gu: University of Science and Technology of China
Cheng Cheng: University of Science and Technology of China
Qingrui Zha: University of Science and Technology of China
Shengwei Tao: University of Science and Technology of China
Yunguang Zhang: University of Science and Technology of China
Junhui Chu: University of Science and Technology of China
Chenghui Wu: University of Science and Technology of China
Yuchen Zhang: University of Science and Technology of China
Jiabei Wang: University of Science and Technology of China
Yao Liu: University of Science and Technology of China
Lianxin Liu: The First Affiliated Hospital of Harbin Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58429-7

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