NS3 of hepatitis C virus drives hepatocellular carcinoma progression through a novel RNA‐interference pathway

Hepatocellular carcinoma (HCC), a severe consequence of hepatitis C virus infection, is significantly influenced by the virus's non-structural protein 3 (NS3). This study employed transcriptome sequencing to explore the role of NS3 in promoting HCC progression by comparing gene expression profiles between HCV-infected HCC tissues and healthy liver controls. Key genes regulated by NS3 were identified and validated with quantitative reverse transcription PCR (RT-qPCR) and western blot analyses. Functionality assays, including CCK-8, BrdU, and Transwell migration and invasion tests, were performed to evaluate the effects of NS3 on HCC cell proliferation, migration, and invasion. Further investigation through a dual-luciferase reporter and RNA pull-down assays revealed that NS3 specifically upregulates circ_0001175. This circular RNA interacts with and inhibits miR-130a-5p, diminishing its regulatory impact on P53 by modulating the MDM4 pathway, thereby promoting oncogenic characteristics. The findings highlight the NS3-induced circ_0001175/miR-130a-5p/MDM4/P53 pathway as a potential therapeutic target, offering promising directions for treatment strategies in HCV-related HCC.