SPI1 Transcriptional Activates TXNRD1 to Protect Trophoblast Cell from Ferroptosis.

IF 2.5 3区 医学 Q2 OBSTETRICS & GYNECOLOGY
Reproductive Sciences Pub Date : 2025-09-01 Epub Date: 2025-08-18 DOI:10.1007/s43032-025-01945-0
Tiantian Chen, Ruxiu Ge, Jie Bai, Haiteng Ye
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引用次数: 0

Abstract

Preeclampsia (PE) is a severe complication of pregnancy characterized by hypertension and organ dysfunction. Abnormal low expression of thioredoxin reductase 1 (TXNRD1) in the placenta has been implicated in the pathogenesis of PE. This study aimed to investigate the role of TXNRD1 in PE and its association with ferroptosis. In our study, placental tissues collected from healthy pregnant women and PE patients, as well as trophoblast cell lines (HTR-8 and JEG-3) were employed in this study. QPCR, Western blot, and immunohistochemistry (IHC) were performed to detect the genes expression. Additionally, ferroptosis level was tested by assessing cell activity, reactive oxygen species (ROS) levels, lipid oxidation, and key ferroptosis-related proteins. The transcriptional regulation mechanism of TXNRD1 was explored using bioinformatics tools, dual luciferase reporter assay, ChIP-qPCR, and electrophoretic mobility shift assay (EMSA). Our results showed that TXNRD1 expression was significantly lower in the placenta of PE patients compared to healthy controls. Consistently, the protein levels of GPX4 and SLC7A11, which are inhibitors of ferroptosis, were reduced in PE, while the levels of COX2 and ACSL4, promoters of ferroptosis, was increased. Overexpression of TXNRD1 in trophoblast cells enhanced ferroptosis resistance, as evidenced by increased cell activity, reduced ROS levels, inhibited lipid oxidation, and altered expression of ferroptosis-related proteins. Conversely, knocking down TXNRD1 exacerbated erastin-induced ferroptosis. Furthermore, we identified SPI1 as a transcriptional activator of TXNRD1, which was also abnormally low expressed in the placenta of PE patients. Overexpression of SPI1 protected trophoblast cells from ferroptosis, which was reversed by inhibiting TXNRD1 expression. Collectively, our findings reveal that SPI1-mediated transcriptional regulation of TXNRD1 plays a protective role in ferroptosis of trophoblast cell, and impeded TXNRD1 expression might involve in PE, advancing our understanding of its pathogenesis.

SPI1转录激活TXNRD1保护滋养细胞免于铁下垂。
子痫前期(PE)是一种以高血压和器官功能障碍为特征的严重妊娠并发症。胎盘中硫氧还蛋白还原酶1 (TXNRD1)的异常低表达与PE的发病机制有关。本研究旨在探讨TXNRD1在PE中的作用及其与铁下垂的关系。在我们的研究中,我们收集了健康孕妇和PE患者的胎盘组织,以及滋养细胞(HTR-8和JEG-3)。采用QPCR、Western blot和免疫组化(IHC)检测基因表达。此外,通过评估细胞活性、活性氧(ROS)水平、脂质氧化和关键的铁中毒相关蛋白来检测铁中毒水平。利用生物信息学工具、双荧光素酶报告基因实验、ChIP-qPCR和电泳迁移转移实验(EMSA)探索TXNRD1的转录调控机制。我们的研究结果显示,与健康对照组相比,PE患者胎盘中的TXNRD1表达明显降低。与此一致的是,作为铁下垂抑制因子的GPX4和SLC7A11蛋白水平在PE中降低,而作为铁下垂促进因子的COX2和ACSL4蛋白水平则升高。滋养细胞中TXNRD1的过表达增强了对铁沉的抵抗力,这可以通过细胞活性增加、ROS水平降低、脂质氧化抑制和铁沉相关蛋白表达改变来证明。相反,敲低TXNRD1会加重erastin诱导的铁下垂。此外,我们发现SPI1是TXNRD1的转录激活因子,TXNRD1在PE患者的胎盘中也异常低表达。SPI1过表达可保护滋养细胞免于铁下垂,而抑制TXNRD1表达可逆转这一作用。综上所述,我们的研究结果表明spi1介导的TXNRD1转录调控在滋养细胞铁凋亡中起保护作用,而TXNRD1表达受阻可能与PE有关,从而促进了我们对其发病机制的理解。
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
Reproductive Sciences
Reproductive Sciences 医学-妇产科学
CiteScore
5.50
自引率
3.40%
发文量
322
审稿时长
4-8 weeks
期刊介绍: Reproductive Sciences (RS) is a peer-reviewed, monthly journal publishing original research and reviews in obstetrics and gynecology. RS is multi-disciplinary and includes research in basic reproductive biology and medicine, maternal-fetal medicine, obstetrics, gynecology, reproductive endocrinology, urogynecology, fertility/infertility, embryology, gynecologic/reproductive oncology, developmental biology, stem cell research, molecular/cellular biology and other related fields.
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