Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with a dismal prognosis, underscoring the need to identify previously unrecognized molecular regulators involved in ICC progression. Although human endogenous retroviruses (HERVs) are aberrantly activated in multiple malignancies, their role in ICC remains poorly defined. Here, through integrative profiling of bulk and single-cell transcriptomes, we identified HERV2365 as a key upregulated oncogenic factor, which was enriched in ICC malignant cells and associated with poor prognosis. Functional assays demonstrated that HERV2365 enhanced ICC proliferation and tumorigenesis both in vitro and in vivo . Mechanistically, HERV2365 sponged miR-326, thereby derepressing fibroblast growth factor 1 (FGF1) and promoting tumor growth. Collectively, our findings identified HERV2365 as an unfavorable prognostic marker by promoting ICC progression through regulating the miR-326/FGF1 axis. Hepatology; Molecular biology; Cancer