GGCT Inhibits Ferroptosis in PTC Cells by Upregulating p53 Through RPS15A

γ-Glutamine cyclotransferase (GGCT) is an enzyme involved in the metabolic cycle of glutathione (GSH). Abnormal GSH metabolism is mostly related to ferroptosis. However, the mechanisms supporting aberrant GGCT expression in PTC remain to be investigated. In this study, we found that GGCT knockdown inhibited GSH synthesis and promoted malondialdehyde (MDA) and reactive oxygen species (ROS) accumulation, thereby promoting ferroptosis in papillary thyroid cancer cells. Pro-GA, the specific inhibitor of GGCT, inhibited the subcutaneous tumor formation of K1 cells. IP combined with LC–MS/MS showed an interaction between GGCT and RPS15A. RPS15A is highly expressed in PTC tissues and cells, and GGCT promotes the stability of RPS15A. Knockdown of RPS15A promoted p53 expression, which in turn inhibited SLC7A11 expression, resulting in ferroptosis, while overexpression of RPS15A reversed GGCT-induced ferroptosis. In addition, miR-205-5p targeted the 3’ UTR of GGCT to inhibit GGCT-mediated ferroptosis, tumor growth, and lung metastasis. In conclusion, we found that knockdown of GGCT promoted ferroptosis in PTC cells. Mechanistically, GGCT interacts with RPS15A, and GGCT promotes the protein stability of RPS15A. Knockdown of RPS15A promotes p53 expression and inhibits SLC7A11 expression, thereby inhibiting GSH synthesis. The upstream mechanism of GGCT regulation showed that miR-205-5p inhibited GGCT protein expression by targeting the 3′ UTR of GGCT.