Identification of novel immune ferroptosis-specific genes associated with prognostic features in hepatocellular carcinoma

Background:As the most common iron metabolism and storage organ,the specific regulatory mechanism and prognostic relevance of hepatocellular carcinoma(HCc)need further study.Objective:We aimed to perform a multi-omics integration and a ferroptosis-associated signature of HCC.Methods:Gene Expression Omnibus was searched for available data with ferroptosis inducers,and three independent datasets(GSE104462,GSE112384,and GSE142591)were collected.Multi-omic data with available clinical information of TCGA-LIHC and CHCC were retrieved from the Cancer Genome Atlas(TCGA,http://cancergenome.nih.gov/)and iProX database(www.iprox.org,IPx0000937000).Integrated multi-omics analyses revealed the difference among biological functions,the activation status of key signaling pathways,tumor microenvironment,and sorafenib resistance in HCC.Single-sample gene set enrichment analysis(ssGSEA)identified a novel panel associated with clinical and molecular attributes,including survival,immune microenvironment,sorafenib resistance,genetic profile,liver-specific proteome,and phosphoproteome.Results:We performed a multi-omics integrationfor ferroptosis-associated characterization of HCC using paired tumor and adjacent liver tissues from 370 samples of TCGA.We proposed a novel panel including twelve genes that could reflect the prognosis and capacity of ferroptosis(ATAD2,DTL,DUT,E2F2,GINS2,FOXK1,MCM4,MCM5,MTHFD1,PHF19,POLA1,THOC6).Samples with high ferroptosis prognostic scores suggested significantly inferior survival(P=0.0028),a lower degree of ferroptosis(P<0.001),and greater ferroptosis induction capacity(P<0.001).Conclusion:The score in our study revealed the inherent state and further potential of ferroptosis in tumor cells,which also distinct features in tumor metabolism,microenvironment,clinical phenotype,and potential therapeutics.