2. Academic Validation
  3. Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation

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

  • Nat Commun. 2025 Apr 3;16(1):3177. doi: 10.1038/s41467-025-58429-7.
Ning Zhang # 1,  Linmao Sun # 2 3 4,  Shuo Zhou # 3 4 5,  Changyong Ji # 2 3 4,  Tianming Cui # 2 3 4,  Qi Chu 2 3 4,  Jiareng Ye 2 3 4,  Shuhang Liang 3 4 6,  Kun Ma 2 3 4,  Yufeng Liu 2 3 4,  Xianying Li 3 4 7,  Xinyu Guo 1 8 9,  Weizhi Zhang 1 3 4,  Xuetian Gu 2 3 4,  Cheng Cheng 2 3 4,  Qingrui Zha 2 3 4,  Shengwei Tao 2 3 4,  Yunguang Zhang 2 3 4,  Junhui Chu 2 3 4,  Chenghui Wu 2 3 4,  Yuchen Zhang 2 3 4,  Jiabei Wang 10 11 12,  Yao Liu 13 14 15,  Lianxin Liu 16
Affiliations

Affiliations

  • 1 Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China.
  • 4 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China.
  • 5 Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.
  • 6 Department of Gastrointestinal Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 7 Hepatobiliary Surgery Department, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China.
  • 8 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 9 Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, China.
  • 10 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. jbwang16@ustc.edu.cn.
  • 11 Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China. jbwang16@ustc.edu.cn.
  • 12 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China. jbwang16@ustc.edu.cn.
  • 13 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. liuyao66@ustc.edu.cn.
  • 14 Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China. liuyao66@ustc.edu.cn.
  • 15 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, China. liuyao66@ustc.edu.cn.
  • 16 Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. liulx@ustc.edu.cn.
  • # Contributed equally.
PMID: 40180922 DOI: 10.1038/s41467-025-58429-7
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.

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