Novel prognostic signature based on HRAS, MAPK3 and TFRC identified to be associated with ferroptosis and the immune microenvironment in hepatocellular carcinoma

Objectives: Ferroptosis, a programmed cell death, has been recognized recently. Several studies have shown the connection between ferroptosis and biological processes in cancer. However, the potential role and mechanism of ferroptosis-related genes in hepatocellular carcinoma (HCC) remain unclear, and understanding the crosstalk between the tumor immune microenvironment and ferroptosis is still a great challenge. Method: We retrospectively analyzed the transcriptomic and clinical data of HCC from TCGA database. 74 ferroptosis-related genes (FRGs), including 14 immune-ferroptosis-related genes (IFRGs), were identified with differential expression in tumor and normal tissues. Then, we screened and constructed a prognostic signature using survival analysis and the least absolute shrinkage and selection operator. Furthermore, we validated the performance of the signature for assessing survival prognosis and clinicopathological staging. In addition, we investigated the link between the prognostic features and tumor-infiltrating immune cells using CIBERSORT. Result: The results identified HRAS, MAPK3 and TFRC as prognostic IFRGs. The risk score was elevated when IFRGs were upregulated and patient outcomes worsened. In addition, the results show significant differences in tumor-infiltrating immune cells, especially immuno-suppressive cells, including tumor-infiltrating macrophages cells and regulatory cells, implying that the expression of these three IFRGs may be an intrinsic barrier to strong ferritin-induced immune responses. Enrichment analysis revealed crosstalk between ferroptosis and tumor immunity. The effect of the risk score was validated in the ICGC cohort and the Human Protein Atlas database confirmed the high expression of IFRGs in tumor tissue. Conclusions: In our study, these IFRGs may provide some new ideas for the study of ferroptosis and the tumor immunity. These findings may also provide new strategies for treatment of HCC.

Automated summary

This study identified ferroptosis-related genes (FRGs) and constructed a prognostic signature for hepatocellular carcinoma (HCC). The study also investigated the crosstalk between these genes and tumor-infiltrating immune cells, revealing a connection between ferroptosis and tumor immunity.