2. Academic Validation
  3. Glycochenodeoxycholic acid promotes hepatocarcinogenesis by inducing hepatic progenitor cell differentiation into cancer-associated fibroblasts via sphingosine-1-phosphate receptor 2 signalling

Glycochenodeoxycholic acid promotes hepatocarcinogenesis by inducing hepatic progenitor cell differentiation into cancer-associated fibroblasts via sphingosine-1-phosphate receptor 2 signalling

  • Biomark Res. 2025 Dec 17;13(1):157. doi: 10.1186/s40364-025-00873-0.
Lu Gao # 1 2,  Gang Lv # 3,  Ying Huang # 4 5,  Mengmeng Xue # 6,  Zhipeng Zhang 7 8,  Jing Weng 7,  Haoran Bai 9,  Min Tao 6,  Xi Luo 1 10,  Yuhua Gao 1 10,  Shiyao Feng 11,  Xiaojuan Hou 2,  Chen Zong 2,  Xue Yang 2,  Qiudong Zhao 2,  Jinghua Jiang 2,  Xinyu Zhu 12,  Zhipeng Han 9,  Changtao Jiang 1 10,  Dongyu Zhao 13,  Lixin Wei 14,  Lulu Sun 15 16
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 2 Department of Tumor Immune and Metabolism, National Center for Liver Cancer, Naval Medical University, Shanghai, China.
  • 3 Senior Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 4 State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Third Hospital, Peking University, Beijing, China.
  • 5 Institute of Advanced Clinical Medicine, Peking University, Beijing, China.
  • 6 School of Pharmacy, Anhui Medical University, Hefei, China.
  • 7 Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China.
  • 8 Cancer Center, Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology, Peking University Third Hospital, Peking University, Beijing, China.
  • 9 Department of Oncology, Longhua Hospital Affiliated to , Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 10 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 11 Department of Urology, Chao hu Hospital of Anhui Medical University, Anhui, China.
  • 12 Changhai Clinical Research Unit, Changhai Hospital of Naval Medical University, Shanghai, China.
  • 13 Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China. [email protected].
  • 14 Department of Tumor Immune and Metabolism, National Center for Liver Cancer, Naval Medical University, Shanghai, China. [email protected].
  • 15 State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Third Hospital, Peking University, Beijing, China. [email protected].
  • 16 Institute of Advanced Clinical Medicine, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41408647 DOI: 10.1186/s40364-025-00873-0
Abstract

Background: Patients with advanced hepatocellular carcinoma (HCC) often develop cholestasis and exhibit poor clinical outcomes. Current evidence suggests that dysregulated bile acid metabolism may contribute to HCC progression, although the underlying molecular mechanisms remain unclear. Among the bile acids, glycochenodeoxycholic acid (GCDCA) is a key component of cholestasis. Under pathological conditions, hepatic progenitor cells (HPCs) transform into fibroblasts or tumor-initiating cells, directly promoting liver fibrosis and HCC development. This study aimed to investigate the regulatory role of GCDCA in the activation and differentiation of HPCs to elucidate its potential mechanisms in hepatocarcinogenesis.

Methods: Single-cell RNA Sequencing was used to infer the heterogeneity of cancer-associated fibroblasts (CAFs) and their differentiation relationship with HPCs in a diethylnitrosamine-induced rat model. The TCGA and GEO datasets were used to assess the prognostic value of inflammatory CAFs (iCAFs) in patients with HCC. Transcriptomic Sequencing, functional assays, and in vivo experiments were performed to validate the role of GCDCA in HCC pathogenesis.

Results: We identified a CAF subset closely associated with the development of HCC (PDGFRA+CAFs). GCDCA promotes the differentiation of HPCs into PDGFRA+CAFs, which is mediated by sphingosine-1-phosphate receptor 2 (S1PR2). Treatment with the S1PR2 inhibitor JTE-013 markedly inhibited the progression of the pro-fibrotic phenotype in HPCs, which consequently reduced tumor growth and fibrosis in rats.

Conclusions: GCDCA-induced differentiation of HPCs into PDGFRA+CAFs plays a critical role in HCC progression, driven by the S1PR2 receptor. These results provide new insights into the mechanisms underlying HPCs-mediated hepatocarcinogenesis. Targeting S1PR2 represents a promising therapeutic strategy for HCC with potential benefits in reducing fibrosis and tumorigenesis.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40364-025-00873-0.

Keywords

Cancer-associated fibroblasts; Glycochenodeoxycholic acid; Hepatic progenitor cells; Hepatocellular carcinoma; Sphingosine-1-phosphate receptor 2.

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