TRIM25 facilitates ferroptosis in ovarian cancer through promoting PIEZO1 K63-linked ubiquitination and degradation

IF 5 2区医学 Q2 Medicine Translational Oncology Pub Date : 2025-06-01 Epub Date: 2025-04-18 DOI:10.1016/j.tranon.2025.102386

Ya Li, Fei Zhou, Zhengmei Xu

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Abstract

Background

Ovarian cancer represents a significant threat to women's health. and ferroptosis is recognized as a potential natural inhibitor in cancer therapy, the regulatory mechanism of TRIM25 in ovarian cancer and its potential for regulating ferroptosis as a treatment remain unclear.

Methods

The role of TRIM25 in ovarian cancer was examined through functional gain- and loss-of-function assays both in vitro and in vivo, while its target genes were identified. The stability and ubiquitination sites of PIEZO1 were analyzed using protein docking and ubiquitination experiments.

Results

TRIM25 is highly expressed in ovarian cancer and promotes the growth and metastasis of ovarian cancer cells both in vivo and in vitro. Mechanistically, it facilitates PIEZO1 degradation through ubiquitination-dependent proteasome activity, inhibits ferroptosis, and stimulates ovarian cancer cell growth.

Conclusion

Our study clearly shows that TRIM25 stimulates ovarian cancer by inducing K63-linked ubiquitination of PIEZO1, which suppresses ferroptosis and promotes excessive proliferation of ovarian cancer cells. Further research identified the ubiquitination modification site on PIEZO1, providing insights for ovarian cancer treatment.

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TRIM25通过促进PIEZO1 k63连接的泛素化和降解，促进卵巢癌铁下垂

背景：卵巢癌是对妇女健康的重大威胁。尽管铁下垂被认为是一种潜在的天然肿瘤治疗抑制剂，TRIM25在卵巢癌中的调节机制及其调节铁下垂作为治疗手段的潜力仍不清楚。方法通过体外和体内功能增加和功能丧失实验，研究TRIM25在卵巢癌中的作用，并鉴定其靶基因。通过蛋白对接和泛素化实验分析PIEZO1的稳定性和泛素化位点。结果strim25在卵巢癌中高表达，在体内和体外均能促进卵巢癌细胞的生长和转移。机制上，它通过泛素化依赖的蛋白酶体活性促进PIEZO1降解，抑制铁下垂，刺激卵巢癌细胞生长。结论我们的研究清楚地表明，TRIM25通过诱导PIEZO1的k63连锁泛素化来刺激卵巢癌，从而抑制铁凋亡，促进卵巢癌细胞过度增殖。进一步的研究确定了PIEZO1上的泛素化修饰位点，为卵巢癌的治疗提供了新的见解。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.