Cell cycle checkpoint-related genes (CCCRGs) are implicated in the development and progression of hepatocellular carcinoma (HCC). However, their precise roles and underlying mechanisms remain insufficiently characterized and require further investigation. This study aimed to explore the prognostic significance of CCCRGs in HCC, and to investigate the mechanism by which they promote the progression of HCC.

HCC datasets from The Cancer Genome Atlas and International Cancer Genome Consortium were analyzed to identify hub genes. A prognostic model was constructed and validated using Kaplan–Meier analysis, nomogram, calibration curves, decision curve analysis, and receiver operating characteristic analysis. Immune infiltration patterns were assessed using single sample gene set enrichment analysis, while pathway activities were evaluated via gene set variation analysis. Single-cell RNA sequencing data from GSE149614 were analyzed with Seurat and CellChat to investigate cell–cell communication. Patient-derived HCC specimens were examined through immunohistological evaluation, HCC cell lines were used for in vitro functional assays, and in vivo tumor growth was assessed through animal experiments.

CCCRGs showed significant associations with prognosis, malignant biological behavior, and immune responses in HCC. Centromere protein (CENP) I was identified as a critical hub gene that markedly promoted HCC proliferation, metastasis, and epithelial–mesenchymal transition, while inhibiting apoptosis. Mechanistically, CENPI suppressed YAP phosphorylation, enhancing its nuclear translocation and thereby driving malignant progression. Additionally, CENPI impaired immune effector cell infiltration, likely by disrupting tumor antigen presentation and chemokine-mediated CD8+ T cell chemotaxis, thereby promoting immune escape.

This study underscores the prognostic significance of CCCRGs in HCC and identifies CENPI as a key driver of tumor progression through the Hippo pathway. Furthermore, it reveals CENPI’s role in promoting immune escape, suggesting novel therapeutic targets for HCC treatment.