Establishment and validation of a ferroptosis-related prognostic signature for hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high heterogeneity. The prognosis of HCC is quite poor and the prognostic prediction also has challenges. Ferroptosis is recently recognized as a kind of iron-dependent cell death, which is involved in tumor progression. However, further study is needed to validate the influence of drivers of ferroptosis (DOFs) on the prognosis of HCC.

Methods: The FerrDb database and the Cancer Genome Atlas (TCGA) database were applied to retrieve DOFs and information of HCC patients respectively. HCC patients were randomly divided into training and testing cohorts with a 7:3 ratio. Univariate Cox regression, LASSO and multivariate Cox regression analyses were carried out to identify the optimal prognosis model and calculate the risk score. Then, univariate and multivariate Cox regression analyses were performed to assess the independence of the signature. At last, gene functional, tumor mutation and immune-related analyses were conducted to explore the underlying mechanism. Internal and external databases were used to confirm the results. Finally, the tumor tissue and normal tissue from HCC patients were applied to validate the gene expression in the model.

Results: Five genes were identified to develop as a prognostic signature in the training cohort relying on the comprehensive analysis. Univariate and multivariate Cox regression analyses confirmed that the risk score was able to be an independent factor for the prognosis of HCC patients. Low-risk patients showed better overall survival than high-risk patients. Receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. Furthermore, internal and external cohorts were consistent with our results. There was a higher proportion of nTreg cell, Th1 cell, macrophage, exhausted cell and CD8T cell in the high-risk group. The Tumor Immune Dysfunction and Exclusion (TIDE) score suggested that high-risk patients could respond better to immunotherapy. Besides, the experimental results showed that some genes were differentially expressed between tumor and normal tissues.

Conclusion: In summary, the five ferroptosis gene signature showed potential in prognosis of patients with HCC and could also be regarded as a value biomarker for immunotherapy response in these patients.