OLFM4 promotes intrahepatic cholangiocarcinoma progression through a PKM2-glycolysis-histone lactylation feedback loop.
6 affiliations
- 1Department of Hepatobiliary Surgery, The First Affiliated Hospital with Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu Province, China.
- 2The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu Province, China.
- 3Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- 4Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, China.
- 5Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
- 6Jiangsu Provincial Key Laboratory of Chronic Digestive Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, China.
Abstract
Metabolic reprogramming is increasingly recognized as a key characteristic of intrahepatic cholangiocarcinoma (ICC) initiation and progression. Among these metabolic alterations, glycolysis is central for supporting tumor growth. Elucidating the precise molecular mechanisms of glycolysis in ICC is critical for developing precision therapies. Here, comprehensive integrative analyses revealed that olfactomedin 4 (OLFM4) is upregulated in ICC specimens and is associated with adverse patient outcomes. Mechanistically, OLFM4 promotes ICC progression by recruiting ubiquitin specific peptidase 10 (USP10) to stabilize pyruvate kinase M2 (PKM2). This interaction enhances glycolysis and lactate production, thereby elevating histone lactylation, with a prominent impact on H3K18 lactylation (H3K18la). Consequently, H3K18la positively regulates OLFM4 transcription, establishing a positive glycolysis-histone lactylation feedback loop. Notably, tiliroside, a candidate pharmacological inhibitor of OLFM4, demonstrated antitumor efficacy in ICC. Collectively, these findings support targeting OLFM4 as a promising therapeutic strategy for ICC management.
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BibTeX
@article{liu2026olfm4,
title = {{OLFM4 promotes intrahepatic cholangiocarcinoma progression through a PKM2-glycolysis-histone lactylation feedback loop.}},
author = {Shuochen Liu and Kai Cao and Changan Chen and Xiao Xu and Jijun Shan and Chang Li and Ruixiang Chen and Yananlan Chen and Jiang Chang and Wangjie Jiang and Yaodong Zhang and Dong Wang and Changxian Li and Xiangcheng Li},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.135505},
url = {https://europepmc.org/article/MED/42910221},
note = {CC BY},
}
RIS
TY - JOUR
TI - OLFM4 promotes intrahepatic cholangiocarcinoma progression through a PKM2-glycolysis-histone lactylation feedback loop.
AU - Shuochen Liu
AU - Kai Cao
AU - Changan Chen
AU - Xiao Xu
AU - Jijun Shan
AU - Chang Li
AU - Ruixiang Chen
AU - Yananlan Chen
AU - Jiang Chang
AU - Wangjie Jiang
AU - Yaodong Zhang
AU - Dong Wang
AU - Changxian Li
AU - Xiangcheng Li
PY - 2026
DA - 2026/09/18
JO - International journal of biological sciences
DO - 10.7150/ijbs.135505
UR - https://europepmc.org/article/MED/42910221
AB - Metabolic reprogramming is increasingly recognized as a key characteristic of intrahepatic cholangiocarcinoma (ICC) initiation and progression. Among these metabolic alterations, glycolysis is central for supporting tumor growth. Elucidating the precise molecular mechanisms of glycolysis in ICC is critical for developing precision therapies. Here, comprehensive integrative analyses revealed that olfactomedin 4 (OLFM4) is upregulated in ICC specimens and is associated with adverse patient outcomes. Mechanistically, OLFM4 promotes ICC progression by recruiting ubiquitin specific peptidase 10 (USP10) to stabilize pyruvate kinase M2 (PKM2). This interaction enhances glycolysis and lactate production, thereby elevating histone lactylation, with a prominent impact on H3K18 lactylation (H3K18la). Consequently, H3K18la positively regulates OLFM4 transcription, establishing a positive glycolysis-histone lactylation feedback loop. Notably, tiliroside, a candidate pharmacological inhibitor of OLFM4, demonstrated antitumor efficacy in ICC. Collectively, these findings support targeting OLFM4 as a promising therapeutic strategy for ICC management.
SN - 1449-2288
ER -