Abstract
BRD4, a member of the BET family proteins, is extensively studied in cancer and is known for its complex network within tumor cells, interacting with various transcription factors and epigenetic regulatory proteins. However, the impact of BRD4 and its associated genes on hepatocellular carcinoma (HCC) remains unclear. HCC is one of the leading causes of cancer-related deaths globally, often diagnosed at an advanced stage, limiting treatment options. In this study, we curated BRD4-interacting genes and, through analysis of the TCGA-LIHC dataset, developed a four-gene prognostic model for HCC comprising EZH2, KIF20A, G6PD, and KIF2C. This model demonstrated strong predictive power in both training and validation cohorts, with high gene expression levels significantly correlating with poor prognosis. Furthermore, our analysis revealed significant immunological differences between risk groups and identified increased drug sensitivity in high-risk patients to certain medications, while decreased sensitivity to others. Experimental validation further indicated that the combination of BRD4 inhibitor ZBC260 and EZH2 inhibitor CPI-169 synergistically enhanced apoptosis in HCC. Collectively, this study provides a scientific rationale for early HCC diagnosis and personalized therapy, offering new insights into drug resistance in treatment.