2. Academic Validation
  3. FGF1-FGFR2 axis regulated by nuclear receptor RORγ represents an effective strategy in intrahepatic cholangiocarcinoma

FGF1-FGFR2 axis regulated by nuclear receptor RORγ represents an effective strategy in intrahepatic cholangiocarcinoma

  • Cell Death Discov. 2025 Dec 22;11(1):562. doi: 10.1038/s41420-025-02844-8.
Zhanfeng Gu # 1,  Xiaojuan Wang # 2,  Hong Wang # 3,  Junhua Wang # 4,  Zhaorong Huang 1,  Dongyue Pan 1 5,  Zhenhua Zhang 3,  Yechun Zeng 3,  Guodi Cai 3,  Huizi Sun 3,  Jun Zheng 1,  Yichu Nie 4,  Qingwen Zhang 6,  Haolong Li 7,  Franky Leung Chan 7,  Junjian Wang 8,  Jianwei Zheng 9,  Yingfang Fan 10
Affiliations

Affiliations

  • 1 Department of Hepatobiliary surgery, The Third Affiliated Hospital, Southern Medical University, Guangdong, 510630, Guangzhou, China.
  • 2 Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, 102218, Beijing, China.
  • 3 National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangdong, 510006, Guangzhou, China.
  • 4 Clinical Research Institute, The First People's Hospital of Foshan, Guangdong, 528000, Foshan, China.
  • 5 The Breast Center, Cancer Hospital of Shantou University Medical College, Guangdong, 515041, Shantou, China.
  • 6 State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao.
  • 7 School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
  • 8 National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangdong, 510006, Guangzhou, China. [email protected].
  • 9 National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangdong, 510006, Guangzhou, China. [email protected].
  • 10 Department of Hepatobiliary surgery, The Third Affiliated Hospital, Southern Medical University, Guangdong, 510630, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41430037 DOI: 10.1038/s41420-025-02844-8
Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with limited therapeutic options. Although targeted therapies like pemigatinib provide partial clinical benefits, acquired resistance remains a significant challenge. Through integrative bioinformatics analysis of public datasets and immunohistochemical validation, we identified the retinoid-related Orphan Receptor gamma (RORγ) as markedly upregulated in iCCA. Genetic silencing and pharmacological inhibition of RORγ (GSK805/XY101) suppressed proliferation, induced Apoptosis in vitro, and significantly reduced xenograft tumor growth in vivo. Mechanistically, RORγ promoted Fibroblast Growth Factor receptor 2 (FGFR2) signaling via two complementary mechanisms: direct transcriptional activation of FGFR2 and induction of Fibroblast Growth Factor 1 (FGF1) expression and secretion, which in turn activated FGFR2. Inhibition of RORγ markedly decreased FGF1 levels in conditioned media, whereas exogenous FGF1 restored tumor growth. Notably, RORγ antagonists synergized with pemigatinib to overcome resistance in pemigatinib-refractory models. Collectively, these findings identify the RORγ-FGF1-FGFR2 axis as a critical oncogenic driver in iCCA and highlight RORγ inhibition as a promising therapeutic strategy to suppress tumor progression and enhance sensitivity to FGFR inhibitors.

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