Hypoxia-induced BHLHE41 promotes intrahepatic cholangiocarcinoma progression by enhancing fatty acid synthesis via upregulating ACLY.

Intrahepatic cholangiocarcinoma (ICC) remains one of the most aggressive human malignancies, with its pathogenesis critically influenced by the hypoxic tumor microenvironment. Through RNA sequencing of clinical samples and hypoxia-exposed ICC cells, we identified basic helix-loop-helix transcription factor 41 (BHLHE41) as a significantly upregulated gene. Functional studies demonstrated that, by reprogramming fatty acid synthesis, hypoxia-induced BHLHE41 promotes the proliferation and migration of ICC cells. Combined CUT&Tag and RNA sequencing analyses confirmed that BHLHE41 directly targets and transcriptionally activates ATP citrate lyase (ACLY). This study elucidates that BHLHE41, by orchestrating ACLY transcription, promotes malignant progression and chemoresistance in hypoxic ICC, positioning it as a candidate oncogene and prognostic biomarker.