Iodine-131 induces ferroptosis and synergizes with sulfasalazine in differentiated thyroid cancer cells via suppressing SLC7A11

Iodine-131 (¹³¹I) 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 ¹³¹I to trigger ferroptosis in DTC and to assess the synergistic therapeutic impact of combining ¹³¹I 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 ¹³¹I and SAS on cellular functions. Ferrostatin-1 (Fer-1) reversed the cell viability and colony formation ability inhibited by ¹³¹I. ¹³¹I led to an elevation in the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation. DTC cells exposed to ¹³¹I 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 (<i>GPX4</i>) and solute carrier family 7 member 11 (<i>SLC7A11</i>) in the cells treated with ¹³¹I. The CI values for the combination of SAS and ¹³¹I in DTC cells were less than 1, demonstrating that SAS synergized with ¹³¹I. Moreover, the combination of SAS and ¹³¹I significantly increased the MDA levels and lipid peroxidation, decreased the GSH levels, and suppressed the expression of SLC7A11 and GPX4, while <i>SLC7A11</i> knockdown significantly enhanced ferroptosis-related markers in DTC cells. Animal experiments demonstrated that SAS synergized with ¹³¹I resulted in notable decreases in tumor volume and weight. Furthermore, immunohistochemical analyses revealed that the combination of ¹³¹I and SAS significantly downregulated the expression of GPX4 and SLC7A11 <i>in vivo</i>. Taken together, our results suggest that ¹³¹I may induce lipid peroxidation and ferroptosis, and demonstrate the potential for a synergistic therapeutic effect when ¹³¹I is combined with SAS in the treatment of DTC.