Abstract
INTRODUCTION: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. While *C-myc* is known to drive hepatocarcinogenesis, the roles of its downstream targets remain unclear. NOP56, a conserved nucleolar protein and *C-myc* target, may contribute to HCC progression. METHODS: We analyzed single-cell and bulk transcriptomic datasets to determine NOP56 expression and clinical significance. Loss-of-function assays in HCC cells, along with xenograft models, were used to evaluate its biological role. Protein interaction and pathway analyses were conducted using co-immunoprecipitation and Western blotting. RESULTS: NOP56 was upregulated in malignant hepatocytes and associated with poor prognosis. NOP56 knockdown inhibited proliferation, colony formation, and migration, induced G0/G1 arrest and apoptosis, and reduced tumor growth in vivo. Mechanistically, NOP56 interacted with fibrillarin (FBL) and activated the PI3K/AKT/CREB pathway. Silencing NOP56 lowered FBL levels and suppressed pathway activity, whereas FBL overexpression partially rescued apoptotic effects. DISCUSSION: NOP56 promotes HCC progression through the NOP56-FBL-PI3K/AKT/CREB axis. These findings reveal a previously unrecognized oncogenic role of nucleolar proteins in HCC and highlight this signaling axis as a promising therapeutic target.