Wu Shaohua, Wang Zhongqin, Wang Lin
Department of Gynecology and Obstetrics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, No. 366, the Taihu Road, Taizhou City, Jiangsu Province 225300, China.
Department of Gynecology and Obstetrics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, No. 366, the Taihu Road, Taizhou City, Jiangsu Province 225300, China.
Tissue Cell. 2025 Jul 22;97:103050. doi: 10.1016/j.tice.2025.103050.
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.
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.
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.
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.
滋养层细胞是一种独特的胎盘细胞类型，对铁死亡敏感。靶向滋养层细胞铁死亡可能对先兆子痫（PE）患者的滋养层细胞损伤具有保护作用。在本研究中，探讨了去泛素化酶泛素特异性蛋白酶7（USP7）在PE期间滋养层细胞铁死亡中的作用。
对滋养层细胞（HTR-8/SVneo）进行缺氧处理以模拟PE中的胎盘状态。检测缺氧处理的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实验后，检测细胞活力、侵袭、迁移和铁死亡等生物学活性。检测NRF2、x-CT和GPX4的表达水平。分析NRF2与USP7之间的结合。
缺氧处理的HTR-8/SVneo细胞中USP7表达降低。缺氧处理的HTR-8/SVneo细胞的细胞活力、侵袭和迁移显著降低，但铁死亡明显增强。艾拉司丁处理刺激铁死亡，而USP7过表达或铁死亡抑制剂可阻断铁死亡。机制上，NRF2与USP7结合，USP7诱导NRF2去泛素化并抑制其降解。USP7过表达上调了缺氧处理的HTR-8/SVneo细胞中的x-CT和GPX4。NRF2敲低抵消了USP7过表达引起的缺氧处理的HTR-8/SVneo细胞生物学特性和铁死亡的变化。
USP7介导的NRF2去泛素化使NRF2稳定并激活xCT/GPX4途径，在PE情况下抑制滋养层细胞铁死亡。本研究突出了一种针对滋养层细胞铁死亡的有前景的策略，并支持开发PE的新疗法。
