Iodine-131 induces ferroptosis and synergizes with sulfasalazine in differentiated thyroid cancer cells via suppressing .

Iodine-131 (I) plays a key role in the treatment of differentiated thyroid cancer (DTC). Ferroptosis represents a form of regulated cell death that is distinct from necrosis and apoptosis, constituting a unique mode of programmed cell death. In this study, we aimed to ascertain the potential of I to trigger ferroptosis in DTC and to assess the synergistic therapeutic impact of combining I with sulfasalazine (SAS), a ferroptosis inducer, in the context of DTC. The FTC-133 and TPC-1 cell lines were employed to evaluate the impact of I and SAS on cellular functions. Ferrostatin-1 (Fer-1) reversed the cell viability and colony formation ability inhibited by I. I led to an elevation in the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation. DTC cells exposed to I displayed characteristic ferroptotic ultrastructure, featuring shrunken mitochondria with increased membrane density. Concurrently, there was a reduction in the content of glutathione (GSH), as well as a downregulation of the expression levels of glutathione peroxidase 4 () and solute carrier family 7 member 11 () in the cells treated with I. The CI values for the combination of SAS and I in DTC cells were less than 1, demonstrating that SAS synergized with I. Moreover, the combination of SAS and I significantly increased the MDA levels and lipid peroxidation, decreased the GSH levels, and suppressed the expression of SLC7A11 and GPX4, while knockdown significantly enhanced ferroptosis-related markers in DTC cells. Animal experiments demonstrated that SAS synergized with I resulted in notable decreases in tumor volume and weight. Furthermore, immunohistochemical analyses revealed that the combination of I and SAS significantly downregulated the expression of GPX4 and SLC7A11 . Taken together, our results suggest that I may induce lipid peroxidation and ferroptosis, and demonstrate the potential for a synergistic therapeutic effect when I is combined with SAS in the treatment of DTC.