A novel signature of combing cuproptosis- with ferroptosis-related genes for prediction of prognosis, immunologic therapy responses and drug sensitivity in hepatocellular carcinoma.

Background: Our study aimed to construct a novel signature (CRFs) of combing cuproptosis-related genes with ferroptosis-related genes for the prediction of the prognosis, responses of immunological therapy, and drug sensitivity of hepatocellular carcinoma (HCC) patients. Methods: The RNA sequencing and corresponding clinical data of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), GSE76427, GSE144269, GSE140580, Cancer Cell Line Encyclopedia (CCLE), and IMvigor210 cohorts. CRFs was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm. The analyses involved in the prognosis, response to immunologic therapy, efficacy of transcatheter arterial chemoembolization (TACE) therapy, and drug sensitivity were performed. Furthermore, the molecular function, somatic mutation, and stemness analyses were further performed between the low- and high-risk groups, respectively. In this study, the statistical analyses were performed by using the diverse packages of R 4.1.3 software and Cytoscape 3.8.0. Results: CRFs included seven genes (G6PD, NRAS, RRM2, SQSTM1, SRXN1, TXNRD1, and ZFP69B). Multivariate Cox regression analyses demonstrated that CRFs were an independent risk factor for prognosis. In addition, these patients in the high-risk group presented with worse prognoses and a significant state of immunosuppression. Moreover, patients in the high-risk group might achieve greater outcomes after receiving immunologic therapy, while patients in the low-risk group are sensitive to TACE. Furthermore, we discovered that patients in the high-risk group may benefit from the administration of sunitinib. In addition, enhanced mRANsi and tumor mutation burden (TMB) yielded in the high-risk group. Additionally, the functions enriched in the low-risk group differed from those in the other group. Conclusion: In summary, CRFs may be regarded not only as a novel biomarker of worse prognosis, but also as an excellent predictor of immunotherapy response, efficacy of TACE and drug sensitivity in HCC, which is worthy of clinical promotion.