Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data Reveal a Novel Prognostic Signature of Combining Cuproptosis- and Ferroptosis-Related Genes in Hepatocellular Carcinoma

As a common malignancy, hepatocellular carcinoma (HCC) proliferation and metastasis could be promoted by ferroptosis and cuproptosis. In this study, we screened out the differentially expressed cuproptosis- and ferroptosis-related genes (CFRGs) and identified the 17 informative prognosis-associated genes. A CFRG scoring model was constructed based on the subtypes identified by consensus clustering analysis and principal component analysis (PCA). Furthermore, the immune profile, expression of immune checkpoint genes (ICGs) and drug susceptibility were also compared between the two CFRG score groups. The results showed that patients with a high CFRG score had higher survival probabilities. The correlation analysis suggested that CFRG scores were negatively correlated with activated CD4.T.cell. The expression patterns of thirty ICGs and the half-maximal inhibitory concentration (IC₅₀) values of 128 drugs displayed significant differences between the two CFRG score groups. A statistically significant difference in the efficacy of sorafenib was found between the two CFRG score groups. Moreover, based on multivariate COX regression analysis and weighted gene co-expression network analysis (WGCNA), we screened DLAT and SLC2A1 as signature genes. Molecular docking analysis revealed that DLAT and SLC2A1 had a strong binding affinity toward camptothecin, rapamycin, dactolisib, and luminespib. The correlation between the CFRG score and single-cell characteristics was further explored. The study depended on our understanding of the biological function of CFRGs in HCC and provided new insights for developing treatment strategies.