Dysregulation of CircZNF79(5) Modulates YBX1 Stability and Selective Autophagy to Drive Hepatocellular Carcinoma Progression

Abstract Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy with limited therapeutic options. Circular RNAs (circRNAs) have emerged as critical regulators in various cancers, including HCC, but their roles in HCC progression remain largely unexplored. Here, the role of circZNF79(5) in HCC progression and its underlying mechanisms is investigated. CircZNF79(5) expression in HCC tissues, cell lines and the serum exosomes is analyzed using qRT‐PCR and FISH, and evaluated its effects on cell proliferation, migration, invasion and apoptosis using CCK8, colony formation, EdU, Transwell and Flow cytometry. CircZNF79(5)’s is verified to be upregulated in HCC, and found that it can promote HCC cells proliferation, migration and invasion, while inhibiting the apoptosis. Mechanistically, circZNF79(5) is found to stabilizes the oncogenic protein YBX1 by recruiting BRCC36, a K63 chain deubiquitinating enzyme, thereby preventing YBX1 from p62‐mediated selective autophagic degradation via the AMPK/mTOR signaling pathway. In vivo studies using subcutaneous and orthotopic tumor models confirmed that circZNF79(5) knockdown reduced tumor growth and YBX1 expression. The findings reveal a novel mechanism by which circZNF79(5) promotes HCC progression through YBX1 stabilization and selective autophagy regulation, highlighting the circZNF79(5)‐YBX1‐BRCC36 axis as a potential therapeutic target for HCC.