The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

BACKGROUND: Ferroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive. METHODS: Based on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated. RESULTS: We identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolism(low)immunity(high) subtype and C2 was metabolism(high)immunity(low) subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy. CONCLUSION: We identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.