GINS4 knockdown facilitates ferroptosis via the p53/SLC7A11/GPX4 pathway in thyroid cancer

Background Go-Ichi-Ni-San complex subunit 4 (GINS4) has been implicated in regulating ferroptosis, but evidence regarding thyroid cancer is scarce. This study aimed to investigate the effects of GINS4 on ferroptosis and the underlying mechanisms in thyroid cancer. Methods Human thyroid cancer cell lines TPC-1 and IHH4 were transfected with GINS4-specific siRNA. Ferroptosis inhibition and p53 pathway validation were performed using ferrostatin-1 (Ferr-1) and pifithrin-α (PFT-α), respectively. Protein-protein interaction (PPI) network analysis was performed to investigate the potential association between GINS4 and ferroptosis-related markers. Results GINS4 knockdown promoted ferroptosis in thyroid cancer cell lines, as reflected by increased reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ levels, as well as reduced mitochondrial membrane potential (MMP). The addition of Ferr-1 reversed the effects of GINS4 knockdown on ferroptosis in thyroid cancer cell lines, suggesting that GINS4 knockdown-induced cell death was mainly attributable to ferroptosis. PPI network analysis identified p53 as a potential hub molecule in the GINS4-associated ferroptosis network, with SLC7A11 and GPX4 as key ferroptosis-related downstream proteins. Western blot analysis confirmed that GINS4 knockdown increased p53 while decreasing SLC7A11 and GPX4 in thyroid cancer cell lines. PFT-α reversed the effects of GINS4 knockdown on the p53/SLC7A11/GPX4 pathway and ferroptosis in thyroid cancer cell lines, indicating that the p53/SLC7A11/GPX4 pathway might contribute to GINS4 knockdown-mediated ferroptosis. Conclusion GINS4 knockdown facilitates ferroptosis through the p53/SLC7A11/GPX4 pathway in thyroid cancer cell lines.