Here, we aimed to identify the impact of the histamine (HA)–histamine receptor H2 (HRH2) signaling pathway on stimulating the secretion of hepatocyte growth factor (HGF) by cancer-associated fibroblasts (CAFs), as well as elucidating the mechanisms through which HGF promotes the progression of cholangiocarcinoma. This evidence concerns the gene HRH2 and cholangiocarcinoma.