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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\u2010GA, the specific inhibitor of GGCT, inhibited the subcutaneous tumor formation of K1 cells. IP combined with LC\u2013MS\/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\u2010induced ferroptosis. In addition, miR\u2010205\u20105p targeted the 3\u2019 UTR of GGCT to inhibit GGCT\u2010mediated 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\u2010205\u20105p inhibited GGCT protein expression by targeting the 3\u2032 UTR of GGCT.<\/jats:p>","DOI":"10.1111\/cas.70039","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T20:59:54Z","timestamp":1741726794000},"page":"1592-1603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>GGCT<\/scp> Inhibits Ferroptosis in <scp>PTC<\/scp> Cells by Upregulating p53 Through <scp>RPS15A<\/scp>"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8602-0867","authenticated-orcid":false,"given":"Hui\u2010min","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Xinxiang Medical University  Xinxiang Henan People's Republic of China"},{"name":"Institute of Biology and Medicine, College of Life and Health Sciences Wuhan University of Science and Technology  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