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<p>Ferroptosis has been identified as a tumor-inhibiting event in a variety of cancers; however, its molecular basis in non-small cell lung cancer (NSCLC) has not been completely elucidated. Notably, glutathione peroxidase 4 (GPX4) plays a crucial role in ferroptosis. Our previous research revealed that prostaglandin E synthase 3 (p23), a potential transcription factor, plays a crucial role in promoting cancer progression and metastasis through succinylation. Our study revealed a previously unknown antiferroptotic function of p23. Mechanistically, p23 stabilizes GPX4 by competitively binding heat shock cognate 71&#xa0;kDa protein (HSC70) to suppress chaperone-mediated autophagy (CMA) activity, which subsequently inhibits ferroptosis and accelerates tumor growth. Notably, impairing p23 succinylation disrupts its interaction with HSC70, restoring CMA-mediated GPX4 degradation. Collectively, our findings suggest that targeting p23-regulated CMA pathways represents a potentially viable strategy to modulate ferroptosis in NSCLC.</p> Graphical Abstract <p>The role of p23 in competing with GPX4 for binding to HSC70, blocking CMA-mediated degradation of GPX4 and inhibiting ferroptosis</p> <p></p>

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P23 acts as a negative regulator of ferroptosis in NSCLC by blocking GPX4 degradation via chaperone-mediated autophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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  • Junlin Chen,
  • Yulin Peng,
  • Meirong Zhou,
  • Yilin Che,
  • Shilei Zhao,
  • Chengjian He,
  • Wen Zhang,
  • Xiangge Tian,
  • Wenhao Zhang,
  • Zhe Liu,
  • Minghao Zhou,
  • Guobiao Liang,
  • Xiaokui Huo,
  • Yan Wang,
  • Zhenlong Yu,
  • Xiaochi Ma

摘要

Ferroptosis has been identified as a tumor-inhibiting event in a variety of cancers; however, its molecular basis in non-small cell lung cancer (NSCLC) has not been completely elucidated. Notably, glutathione peroxidase 4 (GPX4) plays a crucial role in ferroptosis. Our previous research revealed that prostaglandin E synthase 3 (p23), a potential transcription factor, plays a crucial role in promoting cancer progression and metastasis through succinylation. Our study revealed a previously unknown antiferroptotic function of p23. Mechanistically, p23 stabilizes GPX4 by competitively binding heat shock cognate 71 kDa protein (HSC70) to suppress chaperone-mediated autophagy (CMA) activity, which subsequently inhibits ferroptosis and accelerates tumor growth. Notably, impairing p23 succinylation disrupts its interaction with HSC70, restoring CMA-mediated GPX4 degradation. Collectively, our findings suggest that targeting p23-regulated CMA pathways represents a potentially viable strategy to modulate ferroptosis in NSCLC.

Graphical Abstract

The role of p23 in competing with GPX4 for binding to HSC70, blocking CMA-mediated degradation of GPX4 and inhibiting ferroptosis