CENPA as a Genome Stability–Associated Biomarker in Hepatocellular Carcinoma: Multiomics Analysis and Experimental Validation

Genomic instability is closely involved in hepatocellular carcinoma (HCC) progression, but biomarkers that reflect genome stability–related tumor biology and functional vulnerability remain incompletely defined. In this study, we performed an integrative multiomics analysis to identify genome stability–associated candidates in HCC and experimentally evaluated the functional relevance of CENPA. By intersecting genome stability–related genes with differentially expressed and survival‐associated genes in TCGA‐LIHC, we identified a candidate gene set enriched in mitotic regulation, DNA maintenance, and cell‐cycle pathways. A LASSO Cox model was then constructed to derive a 10‐gene prognostic signature. Among these genes, CENPA was selected for focused analysis because of its contribution to the model and its established role in centromere identity and chromosome segregation. CENPA was significantly upregulated in HCC tissues, associated with advanced clinicopathological features, and correlated with unfavorable survival outcomes. Copy‐number and cell‐cycle analyses further linked high CENPA expression to proliferative and genome instability–related molecular states. Functional‐state scoring showed strong associations between CENPA expression and cell‐cycle activity, DNA repair, and DNA damage–related programs. In vitro, CENPA knockdown suppressed HCC cell proliferation, clonogenic growth, and migration. Moreover, CENPA depletion increased cisplatin sensitivity, reduced IC50 values, and induced G2/M accumulation in HCC cell line models. Collectively, these findings suggest that CENPA is a genome stability–associated biomarker and functional contributor to malignant phenotypes in HCC. The cisplatin‐related results further indicate a potential association between CENPA‐dependent mitotic regulation and genotoxic stress response, although in vivo and clinical validation are required to determine its translational significance.