Ferroptosis is an iron-dependent form of cell death. In spite of its significance in pathogenesis and disease progression, ferroptotic signal transduction in HBV-HCC has not been fully explained. Here, four HCC open-source datasets were downloaded from the GEO repository. Cox regression and LASSO models were established to prioritize novel prognostic candidate biomarkers, and the results were verified in vitro and in vivo. We identified 633 common DEGs in both of the bulk RNA-Seq expression profiles. Next, based upon the TCGA-LIHC cohort, a prognostic signature consisting of nine genes was extracted from 633 shared DEGs, and the specificity and sensitivity of the signature were evaluated in both training and validation datasets. This signature showed that the high-risk group had a worse prognosis than the low-risk group. CEP290 was discovered among the prognostic signature genes, and its expression notably correlated with survival, AFP level, TNM stage and vascular invasion. We confirmed expression of CEP290 in eight pairs of HCC tissues and diverse liver cancer cell lines. CEP290 knockdown reduced proliferation, migration and invasion in Hep3B liver cancer cells while Fe2+ and malondialdehyde levels were elevated. Mechanically, co-immunoprecipitation showed an interaction between CEP290 and Nrf2 proteins, and biological phenotypes of Hep3B cells under CEP290 interference were rescued by Nrf2 activator. Furthermore, CEP290 silencing considerably blocked protein expression of Nrf2 pathway members. Finally, suppression of CEP290 effectively inhibited tumor growth in vivo. The above results shed light on the important role of CEP290 in ferroptosis and present an important implication for HCC progression.