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

Zhanfeng Gu1, Xiaojuan Wang2, Hong Wang3

  • 1Department of Hepatobiliary surgery, The Third Affiliated Hospital, Southern Medical University, Guangdong, 510630, Guangzhou, China.

Cell Death Discovery
|December 22, 2025
PubMed

Insights

Retinoid-related orphan receptor gamma (RORγ) drives intrahepatic cholangiocarcinoma (iCCA) growth by activating FGFR2 signaling. Inhibiting RORγ shows promise for treating iCCA and overcoming resistance to targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with few treatment options.
  • Acquired resistance to targeted therapies like pemigatinib is a major clinical challenge.

Purpose of the Study:

  • To identify novel therapeutic targets for iCCA.
  • To investigate the role of retinoid-related orphan receptor gamma (RORγ) in iCCA progression.
  • To explore RORγ inhibition as a strategy to overcome resistance to FGFR inhibitors.

Main Methods:

  • Integrative bioinformatics analysis of public datasets.
  • Immunohistochemical validation in iCCA samples.
  • In vitro and in vivo functional assays using genetic silencing and pharmacological RORγ inhibitors (GSK805/XY101).
  • Analysis of the RORγ-FGFR2 signaling axis, including FGFR2 and FGF1 expression and secretion.

Main Results:

  • RORγ was significantly upregulated in iCCA.
  • RORγ inhibition suppressed iCCA cell proliferation, induced apoptosis, and reduced tumor growth in vivo.
  • RORγ promotes FGFR2 signaling through direct FGFR2 activation and induction of FGF1.
  • RORγ inhibition decreased FGF1 levels, and exogenous FGF1 rescued tumor growth.
  • RORγ antagonists synergized with pemigatinib to overcome pemigatinib resistance.

Conclusions:

  • The RORγ-FGF1-FGFR2 axis is a critical oncogenic driver in iCCA.
  • RORγ inhibition is a potential therapeutic strategy for iCCA.
  • Targeting RORγ may enhance sensitivity to FGFR inhibitors and overcome acquired resistance.

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