Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.
Authors
- Shunrong Ji (ORCID: https://orcid.org/0000-0003-2556-3320)
- Di Wu (ORCID: https://orcid.org/0000-0002-9298-5059)
- Desheng Jing (ORCID: https://orcid.org/0009-0005-4592-0403)
- C YU
- Qifeng Zhuo (ORCID: https://orcid.org/0000-0003-0248-331X)
- Haifeng Hu (ORCID: https://orcid.org/0000-0002-4884-323X)
- Guixiong Fan (ORCID: https://orcid.org/0009-0004-3995-612X)
- Yi Qin (ORCID: https://orcid.org/0000-0001-9804-202X)
- Zhiliang Wang (ORCID: https://orcid.org/0000-0002-7287-8272)
- Zheng Li (ORCID: https://orcid.org/0000-0002-9828-5475)
- Ting Wang (ORCID: https://orcid.org/0000-0001-6532-1110)
- Xiaowu Xu (ORCID: https://orcid.org/0000-0001-5792-9839)
- Borui Li (ORCID: https://orcid.org/0009-0001-3893-0145)
- Chenjie Zhou (ORCID: https://orcid.org/0000-0002-8774-6846)
- Junfeng Xu (ORCID: https://orcid.org/0000-0002-0519-8920)
- Xue-min Chen
Institutions
- University of Science and Technology of China (CN)
- Shanghai Medical College of Fudan University (CN)
- China Three Gorges University (CN)
- Fudan University (CN)
- Soochow University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Cancer Institute (CN)
- First Affiliated Hospital of Chinese PLA General Hospital (CN)
- Hefei First People's Hospital (CN)
Publication Details
- Journal
- Acta Pharmacologica Sinica
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1038/s41401-025-01477-y
- Citations
- 4
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.75
Funders
- Shanghai Anti-Cancer Association
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Hospital Development Center