biostudies-literatureUnknown11(1)Gu ZIntrahepatic 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 fCell death discovery562https://www.ebi.ac.uk/biostudies/studies/S-EPMC12722201biostudies-literatureFGF1-FGFR2 axis regulated by nuclear receptor RORγ represents an effective strategy in intrahepatic cholangiocarcinoma.PMC12722201Li HFan YGu ZWang HZeng YWang JZhang QCai GZheng JPan DHuang ZZhang ZChan FLWang XSun HNie YfalseFGF1-FGFR2 axis regulated by nuclear receptor RORγ represents an effective strategy in intrahepatic cholangiocarcinoma.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 f2025-01-01T00:00:00Z2025 Dec2026-06-08T05:11:52.787Z2026-06-08T03:08:39.783ZS-EPMC127222014143003710.1038/s41420-025-02844-8