Construction and Validation of a Combined Ferroptosis and Hypoxia Prognostic Signature for Hepatocellular Carcinoma

Background: Ferroptosis, as a unique programmed cell death modality, has been found to be closely related to the occurrence and development of hepatocellular carcinoma (HCC). Hypoxia signaling pathway has been found to be extensively involved in the transformation and growth of HCC and to inhibit anti-tumor therapy through various approaches. However, there is no high-throughput study to explore the potential link between ferroptosis and hypoxia, as well as their combined effect on the prognosis of HCC. Methods: We included 370 patients in The Cancer Genome Atlas (TCGA) database and 231 patients in the International Cancer Genome Consortium (ICGC) database. Univariate COX regression and Least Absolute Shrinkage and Selection Operator approach were used to construct ferroptosis-related genes (FRGs) and hypoxia-related genes (HRGs) prognostic signature (FHPS). Kaplan-Meier method and Receiver Operating Characteristic curves were analyzed to evaluate the predictive capability of FHPS. CIBERSOR and single-sample Gene Set Enrichment Analysis were used to explore the connection between FHPS and tumor immune microenvironment. Immunohistochemical staining was used to compare the protein expression of prognostic FRGs and HRGs between normal liver tissue and HCC tissue. In addition, the nomogram was established to facilitate the clinical application of FHPS. Results: Ten FRGs and HRGs were used to establish the FHPS. We found consistent results in the TCGA training cohort, as well as in the independent ICGC validation cohort, that patients in the high-FHPS subgroup had advanced tumor staging, shorter survival time, and higher mortality. Moreover, patients in the high-FHPS subgroup showed ferroptosis suppressive, high hypoxia, and immunosuppression status. Finally, the nomogram showed a strong prognostic capability to predict overall survival (OS) for HCC patients. Conclusion: We developed a novel prognostic signature combining ferroptosis and hypoxia to predict OS, ferroptosis, hypoxia, and immune status, which provides a new idea for individualized treatment of HCC patients.