| Background and Aims: Ferroptosis is a regulatory cell death(RCD)pattern characterized by excessive accumulation of peroxides.Ferroptosis has the potential to improve the efficacy of tumor immunotherapy by regulating the tumor microenvironment(TME).The rapid development of immunotherapy has completely changed the treatment strategy for patients with advanced hepatocellular carcinoma(HCC).However,due to the unique immunosuppressive microenvironment and tumor heterogeneity of HCC,not all HCC patients could benefit from immunotherapy.Therefore,this study will explore the effect of ferroptosis-related genes(FRGs)on the prognosis of HCC patients and the possible mechanism of action.Methods: We collected data from The Cancer Genome Atlas(TCGA)database,Gene Expression Omnibus(GEO)database,and International Cancer Genome Consortium(ICGC)database,containing mRNA expression data and clinical information for 725 HCC patients.A total of 258 FRGs were obtained from the FerrDb database,from which prognostic-related FRGs were identified that were differentially expressed between HCC tissue and adjacent normal tissue.We collected pathological specimens and relevant clinical information from 69 patients undergoing hepatocellular carcinoma surgery.Specific antibodies(18295-1-AP,ab115730,ab37185)were used for immunohistochemical staining of paraffin sections,respectively,to verify the differential expression of key FRGs between HCC tissues and paracancer tissues and their influence on prognosis.We classified ferroptosis molecules in the TCGA-LIHC cohort and GSE76427 cohort by consistent cluster analysis and compared the differences of different molecular subtypes in terms of prognosis,immune infiltration,clinical characteristics,and signaling pathway enrichment.Then,the principal component analysis(PCA)algorithm was used to construct the ferroptosis score,and the patients were divided into high and low ferroptosis score groups.The prognostic value of the ferroptosis score was investigated and validated in the LIRI-JP cohort.The TIDE score was applied to predict the response of different ferroptosis assessment groups to immunotherapy.Results: The three key FRGs(HRAS,SLC7A11,and SLC2A1)screened showed significantly differentially expressed expression between HCC tissues and adjacent normal tissues and were significantly correlated with prognosis.Based on these three key FRGs,we found three distinct ferroptosis molecule classifications in HCC.These subtypes have significant differences in genetic variation,immune infiltration,biological function,and prognosis.Notably,tumors with low ferroptosis scores have features such as immune depletion and widespread tumor mutations,which are associated with a poor prognosis and enhanced response to immunotherapy.Conclusions:1.In this study,three key ferroptosis-related genes(HRAS,SLC7A11,and SLC2A1)were screened by bioinformatics techniques.These three genes were analyzed and verified as independent prognostic factors in hepatocellular carcinoma,providing an innovative way to evaluate the prognosis of patients with hepatocellular carcinoma.2.The potential molecular mechanism of ferroptosis affecting immune invasion and immunotherapy in hepatocellular carcinoma was preliminarily explored.It is suggested that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment.3.The ferroptosis score constructed in this study is an independent prognostic indicator.Assessing the ferroptosis score of individual tumors will help us better understand the characteristics of TME and predict immunotherapy outcomes in HCC patients.We can then formulate a more rational immunotherapy regimen based on this information.In conclusion,the key genes of hepatocellular carcinoma screened by us can not only be used to evaluate the immunotherapy response,TME characteristics,and prognosis of HCC patients,but also serve as the research direction of the molecular mechanism and molecularly targeted drugs of hepatocellular carcinoma in the future. |
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