Irofulven and RSL3 synergistically target ferroptosis-related gene PTGR1 to treat head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive form of cancer characterized by significant fatality rates and unfavorable clinical outcomes. Ferroptosis serves as a crucial mechanism in controlling oncogenesis and tumor growth. However, the strategy targeting ferroptosis-related gene to predict and treat HNSCC is still not clear. The study was designed to assess the potential of ferroptosis as a biomarker and therapeutic target in HNSCC. A prognostic model based on ferroptosis-related genes was constructed using least absolute shrinkage and selection operator (LASSO). Multi-omic analysis revealed that the model was closely related to DNA methylation, DNA mutation and immune infiltration. HNSCC classification and the risk score in each classification were identified by analyzing single-cell RNA-sequencing (scRNA-seq) data. The results demonstrated that the risk score in malignant tumor classification is the highest, which is relative to the progression of HNSCC. Furthermore, through CellMiner database, we found the small molecular drug irofulven could target the risk score-related gene prostaglandin reductase 1 (PTGR1), which could inhibit the ferroptosis levels in HNSCC. Importantly, irofulven and ferroptosis inducer RSL3 exerted significant synergistic effects on HNSCC in vitro and in vivo . Altogether, this study offers a potential strategy for developing a combination therapy for targeting ferroptosis in the treatment of HNSCC.