Auranofin resensitizes ferroptosis-resistant lung cancer cells to ferroptosis inducers.

Lung cancer, a major cause of cancer-related mortality, has limited therapeutic options, especially for advanced cases. Ferroptosis, an iron-dependent form of cell death, is a potential therapeutic strategy for this disease; however, resistance mechanisms in the tumor microenvironment impede its effectiveness. Therefore, in this study, we aimed to investigate the efficacy of sulfasalazine (SAS), a ferroptosis inducer, and auranofin (AUR), a Food and Drug Administration-approved anti-inflammatory agent, combination to counteract ferroptosis resistance in lung cancer. SAS induced ferroptosis in vitro; however, its efficacy in vivo was limited, possibly because of factors, such as nutrient deprivation and high cell density, in the microenvironment that suppressed the activities of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key regulators of ferroptosis resistance. Screening of 2483 drugs revealed AUR as a compound resensitizing the YAP/TAZ-deficient lung cancer cells to ferroptosis. Moreover, SAS and AUR combination significantly enhanced lipid peroxidation and reactive oxygen species accumulation, further driving ferroptosis in cells. This combination effectively inhibited tumor growth and enhanced survival in a murine lung cancer model. Overall, our findings suggest that AUR potentiates ferroptosis-based therapies, serving as an effective candidate to overcome ferroptosis resistance in lung cancer.