Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the fifth most prevalent malignancy worldwide. Disruptions in copper homeostasis adversely affect liver function. Cuproptosis, a recently defined form of regulated cell death triggered by intracellular copper accumulation, disrupts the tricarboxylic acid cycle and mitochondrial respiration. However, the specific roles and mechanisms of cuproptosis-related genes (CRGs) in HCC pathogenesis remain incompletely understood. MATERIALS AND METHODS: We systematically evaluated the expression of 10 CRGs in HCC tissues versus adjacent normal tissues. Bioinformatics analyses included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Gene Set Enrichment Analysis (GSEA) were performed. Immune infiltration levels within the tumor microenvironment were assessed. The prognostic significance of CDKN2A was evaluated using Kaplan-Meier (KM) survival analysis and univariate/multivariate Cox proportional hazards regression. CDKN2A protein expression was validated using immunohistochemistry (IHC). RESULTS: CDKN2A was significantly overexpressed in HCC compared to normal tissues. Bioinformatics analyses implicated CDKN2A in DNA replication, organelle fission, and cell cycle checkpoint signaling. Immune-related analysis revealed that high CDKN2A expression correlated positively with dendritic cell (DC) and Th2 cell infiltration, but negatively with CD8 + T cell and natural killer (NK) cell infiltration. KM analysis demonstrated that high CDKN2A expression predicted significantly shorter overall survival in HCC patients. Univariate and multivariate Cox regression identified CDKN2A as an independent prognostic risk factor. CONCLUSIONS: This study demonstrates that CDKN2A is significantly overexpressed in HCC and plays a role in immune microenvironment modulation. CDKN2A serves as a promising independent prognostic biomarker for HCC, associated with poorer patient survival.