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<p>Ovarian cancer is the most prevalent and deadly gynecological malignancy worldwide, with a 5-year overall survival rate of only 10%–40% for patients with advanced disease. Copper chaperone for superoxide dismutase 1 (CCS) is a metallochaperone that plays a multifaceted role in the maturation of copper and displays aberrant expression levels and functions in cancer. Ferroptosis, a new form of cell death resulting from iron-dependent lipid peroxidation, is closely related to cancer. However, whether CCS regulates ferroptosis in ovarian cancer is unknown, and its underlying mechanisms have not been reported. Here, we report that highly expressed CCS contributes to ovarian cancer tumor growth. Moreover, suppressing CCS induced ferroptosis in ovarian cancer cells and increased their sensitivity to ferroptosis inducers. Mechanistically, high CCS expression was found to reduce intracellular copper ion levels and increase Solute Carrier Family 7 Member 11 (SLC7A11) or Glutathione Peroxidase 4 (GPX4) expression by increasing p53 ubiquitination, thus affecting ferroptosis. Additionally, DC_AC50, a small-molecule inhibitor of CCS that targets its copper transport interface, regulates ferroptosis and ovarian cancer growth. Analysis of clinical data revealed a positive correlation between high CCS expression and high SLC7A11 and GPX4 expression in ovarian cancer patients. In summary, our study reveals that CCS protects ovarian cancer cells from ferroptosis by promoting SLC7A11 and GPX4 expression in a p53-dependent manner.</p>

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CCS facilitates the progression of ovarian cancer by suppressing ferroptotic cell death via the modulation of p53-mediated expression of SLC7A11 and GPX4

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Qi Yan,
  • Ming-ming Sun,
  • Xin-ru Zhai,
  • Hong-kai Chang,
  • Xin-yue Geng,
  • Xiao-bo Zhai,
  • Chen-xin Yang,
  • Yan-ping Li,
  • Tao Wang,
  • Jian-guo Zhao,
  • Tao He,
  • Chang-liang Shan,
  • Shuai Zhang

摘要

Ovarian cancer is the most prevalent and deadly gynecological malignancy worldwide, with a 5-year overall survival rate of only 10%–40% for patients with advanced disease. Copper chaperone for superoxide dismutase 1 (CCS) is a metallochaperone that plays a multifaceted role in the maturation of copper and displays aberrant expression levels and functions in cancer. Ferroptosis, a new form of cell death resulting from iron-dependent lipid peroxidation, is closely related to cancer. However, whether CCS regulates ferroptosis in ovarian cancer is unknown, and its underlying mechanisms have not been reported. Here, we report that highly expressed CCS contributes to ovarian cancer tumor growth. Moreover, suppressing CCS induced ferroptosis in ovarian cancer cells and increased their sensitivity to ferroptosis inducers. Mechanistically, high CCS expression was found to reduce intracellular copper ion levels and increase Solute Carrier Family 7 Member 11 (SLC7A11) or Glutathione Peroxidase 4 (GPX4) expression by increasing p53 ubiquitination, thus affecting ferroptosis. Additionally, DC_AC50, a small-molecule inhibitor of CCS that targets its copper transport interface, regulates ferroptosis and ovarian cancer growth. Analysis of clinical data revealed a positive correlation between high CCS expression and high SLC7A11 and GPX4 expression in ovarian cancer patients. In summary, our study reveals that CCS protects ovarian cancer cells from ferroptosis by promoting SLC7A11 and GPX4 expression in a p53-dependent manner.