Nrf2 targeting in overcoming ferroptosis evasion in head and neck cancer

Ferroptosis is a recently identified type of regulated cell death characterized by lipid peroxidation and redox-active iron accumulation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism, contributing to the evasion of ferroptosis. Inhibiting the Nrf2 pathway has been shown to sensitize cancer cells to ferroptosis. In head and neck cancer cells, we found that activation of the Nrf2-antioxidant responsive element pathway leads to ferroptosis resistance, and inhibiting this pathway reverses ferroptosis evasion. Our study suggests that modulating the Nrf2 pathway could be a promising strategy to overcome resistance in cancer therapy for head and neck cancer. Further research is required to investigate the potential of ferroptosis induction in therapy-resistant head and neck cancer. Targeting Nrf2 through ferroptosis-based cancer therapy may be a novel and effective approach to reverse the resistance of head and neck cancer therapy. •Ferroptosis shows promise in overcoming therapy resistance in head and neck cancer (HNC).•Lipid peroxidation and iron accumulation are key markers of ferroptosis.•The Nrf2 pathway contributes to ferroptosis evasion and resistance in HNC.•Pharmacological inhibition of Nrf2 sensitizes HNC cells to ferroptosis induction.•Targeting Nrf2 to exploit ferroptosis offers a potential approach to reverse therapy resistance in HNC.