Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation
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.
Authors
- Changyong Ji
- Jiabei Wang (ORCID: https://orcid.org/0000-0002-4578-3817)
- Lianxin Liu (ORCID: https://orcid.org/0000-0002-3535-6467)
- Xianying Li (ORCID: https://orcid.org/0000-0002-6483-3461)
- Shengwei Tao
- Yao Liu (ORCID: https://orcid.org/0000-0003-0365-3229)
- Xinyu Guo (ORCID: https://orcid.org/0000-0002-1976-2908)
- Shuhang Liang
- Qi Chu (ORCID: https://orcid.org/0000-0003-3028-0755)
- Jingyang Ye (ORCID: https://orcid.org/0000-0002-7638-9214)
- Xuetian Gu
- Tianming Cui
- Yunguang Zhang
- Yufeng Liu (ORCID: https://orcid.org/0000-0003-2653-3510)
- Yuchen Zhang (ORCID: https://orcid.org/0009-0008-8122-6218)
- Wei Zhang (ORCID: https://orcid.org/0000-0001-8020-4190)
- Kun Ma (ORCID: https://orcid.org/0000-0002-9232-4912)
- Chenghui Wu (ORCID: https://orcid.org/0000-0003-0599-1598)
- Shuo Zhou (ORCID: https://orcid.org/0000-0001-8684-8341)
- Cheng Cheng
- Linmao Sun (ORCID: https://orcid.org/0000-0002-6159-9673)
- Junhui Chu
- Qingrui Zha
- Ning Zhang (ORCID: https://orcid.org/0000-0003-1692-4016)
Institutions
- University of Science and Technology of China (CN)
- Ministry of Education of the People's Republic of China (CN)
- Anhui University (CN)
- Harbin Medical University (CN)
- Sun Yat-sen University (CN)
- Fourth Affiliated Hospital of Harbin Medical University (CN)
- Anhui Provincial Center for Disease Control and Prevention (CN)
- Anhui Provincial Hospital (CN)
- Jining First People's Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- First Affiliated Hospital of Harbin Medical University (CN)
- Shandong First Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1038/s41467-025-58429-7
- Citations
- 14
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 14.64
Funders
- Icahn School of Medicine at Mount Sinai
- Beijing Xisike Clinical Oncology Research Foundation
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Sun Yat-sen University
- University of Science and Technology of China
- Anhui Provincial Department of Education
- National Science and Technology Major Project
- Natural Science Foundation of Anhui Province