Curcumin suppresses head and neck squamous cell carcinoma progression via NCOA4-FTH1-mediated ferroptosis

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent malignancy with limited therapeutic options. Ferroptosis is an iron-mediated type of programmed cell death, and it has surfaced as a viable oncology treatment approach. Curcumin (Cur) is a natural polyphenol that exhibits potent anti-tumor properties; however, the underlying molecular mechanisms regarding cell death modalities in HNSCC remain underexplored. The results of this study show that Cur is an effective Ferroptosis inducer in HNSCC based on transcriptomic Sequencing analysis. Cur treatment triggers hallmark Ferroptosis characteristics that include iron accumulation, lipid peroxidation, radical oxygen species generation, and mitochondrial damage. These effects are all reversed by the Ferroptosis inhibitor ferrostatin-1. Furthermore, we discover that Cur promotes the lysosomal degradation of ferritin heavy chain 1 (FTH1). Specifically, Cur enhances the interaction between the cargo receptor, nuclear receptor coactivator 4 (NCOA4), and FTH1, facilitating ferritinophagy. NCOA4 knockdown blocks FTH1 degradation and rescues HNSCC cells from Cur-induced Ferroptosis. These results demonstrate that Cur triggers Ferroptosis in HNSCC through NCOA4-mediated ferritinophagy. The results of this study highlight the NCOA4-FTH1 axis as a promising therapeutic target and support Cur as a potential candidate for HNSCC treatment.