As one of the most serious types of cancer known, about 600,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed annually (Du et al., 2020, Shield et al., 2017). Given its tendency for metastasis and recurrence, patients with HNSCC need a combined treatment of chemotherapy, radiotherapy, and surgery (Solomon et al., 2018, Muzaffar et al., 2021, Samra et al., 2018). Limited by treatment options, targeted therapies tend to induce tumor-selective cell death while preserving normal tissue. Understanding the molecular mechanisms underlying these protective responses in the context of cellular injury and death may help to enhance clinical therapeutic approaches. Acquisition of various genetic or epigenetic alterations by cancer cells may lead to drug resistance through the activation of stress adaptation responses such as the heat shock response or unfolded protein response (Zhu et al., 2017). In tumor cells, heat shock proteins mainly stabilize the expression of cancer-related mutations and other high-expression protein molecules, and act as molecular chaperones of these proteins to make them biologically active. Heat shock proteins play multiple roles in tumor maintenance and progression, such as promoting the proliferation of cancer cells, reducing cancer cell growth inhibition, promoting cell survival, promoting tumor angiogenesis and the formation of metastases (Calderwood and Gong, 2016). It is crucial to clarify the etiology and mechanism of malignant progression of HNSCC and to explore more effective treatment strategies.

Ferroptosis is a type of programmed cell death (PCD) dependent on iron, and is characterized by the iron-dependent accumulation of lipid-reactive oxygen species (Dixon et al., 2012). Recent decades have seen a rapid increase in research on ferroptosis as it plays a key role in the occurrence and development of tumors (Viswanathan et al., 2017). Many cancer cells are prone to ferroptosis, and small-molecule ferroptosis inducers have a strong inhibitory effect on tumor growth (Ding et al., 2021, Bebber et al., 2021, Yee et al., 2020, Li et al., 2020). In order to meet their growth requirements, tumor cells often have a higher demand for iron than normal cells. This dependence on iron makes tumor cells more prone to iron-catalyzed necrosis. Thus, killing therapy-resistant tumors by inducing ferroptosis is a promising new strategy for cancer therapy (Hassannia et al., 2019). However, there remains a lack of integrated understanding of ferroptosis in HNSCC, including the relationship between ferroptosis regulators and tumor progression. Therefore, finding ferroptosis regulators that precisely induce the death of specific cancer cells may lead to a new potential therapeutic strategy for cancer treatment.

As the effect of ferroptosis-related factors on head and neck squamous cell carcinoma and the underlying mechanisms of the key factors are still unclear, this study aimed to screen key biomarkers for the targeted therapy of HNSCC through the potential role of ferroptosis-related factors in HNSCC and, further, explore the possible mechanisms affecting HNSCC.