목적: Dysregulation of iron-sulfur cluster function increases susceptibility to ferroptosis by elevating the iron-starvation response. However, the impact of glutaredoxin 5 (GRX5) silencing on ferroptosis remains unexplored. This study investigates the role of GRX5 functional loss in enhancing ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. 방법:We assessed the effects of sulfasalazine treatment and the GRX5 gene silencing in HNC cell lines and mouse tumor xenograft models. The analysis included evaluations of cell viability, death, lipid reactive oxygen species (ROS), mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Cystine deprivation, erastin, or sulfasalazine-induced ferroptosis in HNC cells, with relative resistance observed in cisplatin-resistant HNC cells. 결과:Sulfasalazine-induced ferroptosis correlated with increased lipid peroxidation and intracellular free iron, significantly enhanced by short-interfering RNA or short hairpin RNA (shRNA) targeting GRX5 (P<0.05). GRX5 silencing activated the iron-starvation response, elevating intracellular free iron through the iron-responsive element-binding activity of the increased iron regulatory protein (resulting in increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GRX5 cDNA but not by the catalytically inactive mutant GRX5 K101Q. Similar outcomes were observed in an in vivo mouse model transplanted with vector or shGRX5-transduced HNC cells and treated with sulfasalazine. 결론:Our findings suggest that inhibiting GRX5 primes therapy-resistant HNC cells for ferroptosis.