Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

AimsCuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear. MethodsA set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed. ResultsFDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively. SignificanceThe cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.

Automated summary

The study finds that FDX1 is downregulated in hepatocellular carcinoma (HCC), and high expression of FDX1 is associated with longer survival time. HCC patients with high cuproptosis-related risk score (CRRS) have significantly lower overall survival (OS) and are enriched in cancer-related pathways. Mutation analyses reveal high mutational frequency of tumor suppressors such as P53 and BAP1, and low mutational frequency of CTNNB1 in high-CRRS HCC patients. Additionally, high CRRS is associated with increased pro-tumor immune infiltrates and high expression of immune checkpoints. Furthermore, CRRS has a high predictive value in determining the efficiency of sorafenib and non-responsiveness to TACE in HCC patients.