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

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.

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Publication Details

Journal
Molecular Cancer
Published
2025-10-02
DOI
https://doi.org/10.1186/s12943-025-02439-y
Citations
2
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
3.04
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article

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

Xiangge Tian, Xiaochi Ma, Guobiao Liang, Shilei Zhao et al.
2 citations
Molecular Cancer
Ferroptosis and cancer prognosis
3.04
article

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

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

Abstract

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.

Molecular CancerVol. 24(1)
Dalian Medical University (CN), Heilongjiang University of Chinese Medicine (CN), Second Affiliated Hospital of Dalian Medical University (CN), General Hospital of Shenyang Military Region (CN), First Affiliated Hospital of Dalian Medical University (CN), Liaoning Cancer Hospital & Institute (CN)
Openalex Percentile: Top 8%
Ferroptosis and cancer prognosis
3.04
DOIOpen Access PDFOpenAlex
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