USP7 represses ferroptosis in trophoblasts in pre-eclampsia by mediating the xCT/GPX4 axis via deubiquitination of NRF2.

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-12-01 Epub Date: 2025-07-22 DOI:10.1016/j.tice.2025.103050

Shaohua Wu, Zhongqin Wang, Lin Wang

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引用次数: 0

Abstract

Objective: Trophoblasts, a unique placental cell type, are sensitive to ferroptosis. Targeting trophoblast ferroptosis may be protective against trophoblast damage in patients with pre-eclampsia (PE). Herein, this study probed the role of the deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) in trophoblast ferroptosis during PE.

Methods: Trophoblasts (HTR-8/SVneo) were subjected to hypoxia treatment to simulate the placental status in PE. USP7 expression in hypoxia-treated HTR-8/SVneo cells was measured. After gain- and loss-of-function assays in hypoxia-treated HTR-8/SVneo cells, biological activities, such as viability, invasion, migration, and ferroptosis, were detected. NRF2, x-CT, and GPX4 expression levels were examined. The binding between NRF2 and USP7 was analyzed.

Results: USP7 expression was reduced in hypoxia-treated HTR-8/SVneo cells. Cell viability, invasion, and migration were notably decreased, but ferroptosis was markedly enhanced in hypoxia-treated HTR-8/SVneo cells. Erastin treatment stimulated ferroptosis, which was blocked by USP7 overexpression or ferroptosis inhibitor. Mechanistically, NRF2 bound to USP7, and USP7 induced NRF2 deubiquitination and repressed its degradation. Overexpression of USP7 upregulated x-CT and GPX4 in hypoxia-treated HTR-8/SVneo cells. NRF2 knockdown counteracted changes in biological properties and ferroptosis of hypoxia-treated HTR-8/SVneo cells caused by USP7 overexpression.

Conclusion: USP7-mediated NRF2 deubiquitination stabilizes NRF2 and activates the xCT/GPX4 pathway, suppressing trophoblast ferroptosis in the setting of PE. This study highlights a promising strategy against trophoblast ferroptosis and supports the development of new therapies for PE.

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USP7通过NRF2的去泛素化介导xCT/GPX4轴，抑制子痫前期滋养细胞铁凋亡。

目的：滋养细胞是一种独特的胎盘细胞类型，对铁下垂非常敏感。靶向滋养细胞铁下垂可能对子痫前期（PE）患者的滋养细胞损伤有保护作用。本研究探讨了去泛素化酶泛素特异性蛋白酶7 （USP7）在PE过程中滋养细胞铁凋亡中的作用。方法：对滋养细胞HTR-8/SVneo进行缺氧处理，模拟PE中胎盘状态。检测缺氧处理HTR-8/SVneo细胞中USP7的表达。在缺氧处理的HTR-8/SVneo细胞中进行功能获得和功能丧失试验后，检测生物活性，如活力、侵袭、迁移和铁凋亡。检测NRF2、x-CT和GPX4的表达水平。分析了NRF2与USP7的结合。结果：缺氧处理的HTR-8/SVneo细胞中USP7表达降低。缺氧处理的HTR-8/SVneo细胞活力、侵袭性和迁移性明显降低，但铁下垂明显增强。Erastin处理刺激铁下垂，USP7过表达或铁下垂抑制剂阻断铁下垂。机制上，NRF2与USP7结合，USP7诱导NRF2去泛素化并抑制其降解。在缺氧处理的HTR-8/SVneo细胞中，USP7过表达上调x-CT和GPX4。NRF2敲低可抵消USP7过表达引起的缺氧处理HTR-8/SVneo细胞生物学特性和铁凋亡的变化。结论：usp7介导的NRF2去泛素化稳定NRF2，激活xCT/GPX4通路，抑制PE环境下滋养细胞铁凋亡。这项研究强调了一种有希望的对抗滋养细胞铁下垂的策略，并支持PE新疗法的发展。

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

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.