Inhibition of circZFX suppresses malignant phenotypes in cholangiocarcinoma via the miR-654-3p/HDGF and YAP1 signaling activation

Cholangiocarcinoma (CCA) is a highly aggressive hepatobiliary malignancy by a poor prognosis. circular RNAs (circRNAs) have poorly characterized roles in CCA. This study identified that circZFX was significantly upregulated in 4 CCA cell lines and 20 paired CCA/normal tissues. circZFX knockdown suppressed CCA proliferation, migration, and invasion in vitro and reduced xenograft tumor volume by 57% in vivo. Mechanistically, circZFX functions as a competing endogenous RNA for miR-654-3p, thus derepressing HDGF. miR-654-3p inhibitor could reverse the inhibitory effects on the proliferation activity, migration, and invasion capabilities of HuCCT1 and QBC939 cells caused by circZFX silencing. Importantly, co-immunoprecipitation revealed HDGF interaction with YAP1, and circZFX knockdown downregulated YAP1 expression. These findings indicate that inhibition of circZFX suppresses malignant phenotypes in cholangiocarcinoma via the miR-654-3p/HDGF and YAP1 signaling activation, highlighting this axis as a novel therapeutic target and providing mechanistic insights for molecular subtyping and the development of circRNA-based precision therapeutics. CircZFX is upregulated in CCA tissues and cell lines, and promotes CCA progression both in vitro and in vivo. CircZFX sponges miR-654-3p, leading to the de-repression of HDGF. CircZFX drives CCA progression through both the miR-654-3p/HDGF axis and YAP1 activation.