Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma

Ferroptosis resistance is an important mechanism of tumor progression. Interleukin-6 (IL-6) is a representative inflammatory cytokine during chronic inflammation; however, our current understanding of its regulatory role of ferroptosis during carcinogenesis of head and neck squamous cell carcinoma is limited. Chromatin immunoprecipitation and functional observations were performed to investigate xCT-regulatory function of IL-6. We observed a gradual increase in lipid peroxide 4-hydroxynonenal and IL-6 levels during progression from normal oral mucosa to leukoplakia and HNSCC. Meanwhile, the expression of xCT, a key amino acid antiporter assisting ferroptosis resistance, was correlated with IL-6 levels. The upregulated expression of xCT in HNSCC is associated with poor prognosis. Silencing of xCT inhibited HNSCC cell proliferation in vitro and tumor growth in vivo, inducing ferroptosis. Mechanistically, IL-6 transcriptionally activates xCT expression through the JAK2/STAT3 pathway. Furthermore, IL-6 reversed ferroptosis and growth suppression that was induced by xCT knockdown or ferroptosis inducer erastin. Our results demonstrate the critical role of IL-6-induced ferroptosis resistance during HNSCC carcinogenesis. The IL-6/STAT3/xCT axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.