Systematic Expression Analysis of the Ferroptosis and Iron-Metabolism Transcriptomic Profile for Hepatocellular Carcinoma

Abstract

Considering the crucial effects of ferroptosis and iron metabolism on the occurrence and progression of hepatocellular carcinoma (HCC), in this study, we performed a comprehensive analysis of genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. We integrated 104 genes related to ferroptosis and iron metabolism and HCC-related RNA sequencing to identify HCC-related ferroptosis and iron metabolism genes. Through Cox regression and the least absolute shrinkage and selection operator (LASSO) method, we screened four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The prognostic signature was determined to be an independent predictor of prognosis. The diagnostic models were validated in terms of correctly distinguishing between HCC and normal samples, as well as HCC and proliferative nodule samples. In addition, compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression. Through bioinformatics analysis, erastin was showed to affect TH17 cell differentiation and the IL-17 signaling pathway, indicating that erastin is a potential targeted drug for immunotherapy. Funding Statement: This study was supported by National Natural Science Foundation of China (Nos. 81803778), and The Key Research and development Project of Zhejiang Province (No. 2018C03024), and The Public Welfare Research Program of Zhejiang Province (Nos. LQ20H160056 and LGD19h160002), The Natural Science Foundation of Zhejiang Province (No. LYQ20H280003). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The authors reported that since the data of the TCGA database and the ICGC database are open to the public and can be downloaded freely, and this study strictly followed the publication guidelines and access policies of the databases, ethical review and approval from an Ethics Committee are not required for the study.