Iron overload enhances the susceptibility to cysteine deprivation-induced ferroptosis in non-small cell lung cancer cells.

Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation accumulation. Due to the high iron demand of cancer cells, targeting ferroptosis is considered a promising approach for cancer therapy. This study aimed to elucidate the mechanisms underlying the differences in ferroptosis sensitivity in non-small cell lung cancer (NSCLC) cells and identify strategies to overcome ferroptosis resistance. H1299 cells were more sensitive to cysteine deprivation-induced ferroptosis and exhibited higher transferrin receptor (TfR) expression than H460 cells. Transferrin enhanced ferroptosis in cysteine-deprived H1299 cells, while TfR knockdown reduced ferroptosis, suggesting the involvement of TfR/transferrin system in this process. In H460 cells with low TfR expression, transferrin treatment did not induce ferroptosis under cysteine deprivation, indicating that the TfR/transferrin system was not involved. However, treatment with cell-permeable ferric ammonium citrate increased the sensitivity of ferroptosis to cysteine deprivation or RSL3 treatment. In conclusion, iron overload could be a potential strategy to overcome ferroptosis resistance in NSCLC.