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

IF 33.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-10-02 DOI:10.1186/s12943-025-02439-y

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

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

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P23通过伴侣介导的自噬阻断GPX4降解，在NSCLC中作为铁凋亡的负调节因子

铁下垂已被确定为多种癌症的肿瘤抑制事件；然而，其在非小细胞肺癌（NSCLC）中的分子基础尚未完全阐明。值得注意的是，谷胱甘肽过氧化物酶4 （GPX4）在铁下垂中起着至关重要的作用。我们前期的研究发现前列腺素E合成酶3 （p23）是一种潜在的转录因子，通过琥珀酰化在促进癌症的进展和转移中起着至关重要的作用。我们的研究揭示了p23的一种以前未知的反铁亲性功能。机制上，p23通过竞争性结合热休克同源蛋白71kda （HSC70）来稳定GPX4，抑制伴侣介导的自噬（CMA）活性，从而抑制铁凋亡并加速肿瘤生长。值得注意的是，损害p23琥珀酰化破坏了它与HSC70的相互作用，恢复了cma介导的GPX4降解。总之，我们的研究结果表明，靶向p23调节的CMA通路代表了调节非小细胞肺癌铁下垂的潜在可行策略。p23在GPX4与HSC70结合、阻断cma介导的GPX4降解和抑制铁下垂中的竞争作用

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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