NOC2L inhibits trophoblast ferroptosis in preeclampsia through the p53/SLC7A11 pathway

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology Pub Date : 2025-06-04 DOI:10.1016/j.mce.2025.112589

Fengyun Su , Fanhua Shi , Chun Yang , Fei Zhao , Xiaolin Geng , Xiaojing Yang , Xudong Zhao

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引用次数: 0

Abstract

Background

NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear.

Methods

Cell viability, migration, and invasion were determined in hypoxia-stimulated HTR-8/SVneo cells in CCK-8, wound healing, and Transwell assays. The levels of GSH, MDA and Fe²⁺ were measured using specific commercial kits. Lipid ROS levels were determined through C11-BODIPY staining. The protein levels were analyzed via western blotting. Additionally, a rat model of PE was used to examine the influence of NOC2L on the progression of PE and the associated ferroptosis.

Results

NOC2L overexpression increased the viability of hypoxia-treated trophoblast cells and increased the levels of GSH, SLC7A11, and GPX4 while simultaneously reducing Fe²⁺, MDA, and lipid ROS levels. Furthermore, both NOC2L overexpression and ferrostatin-1 application facilitated trophoblast migration and invasion. In contrast, NOC2L knockdown exacerbated the hypoxia-induced increase in ferroptosis and inhibited cell migratory and invasive capabilities. Notably, treatment with PFT-α, a p53 inhibitor, abolished the influence of NOC2L silencing on trophoblast cell functions. NOC2L overexpression was associated with improved blood pressure and urinary protein concentration, reduced pathological damage in the placenta, alterations in ferroptosis-related markers, and an increased survival rate in rat fetuses.

Conclusion

NOC2L inhibits trophoblast ferroptosis through the p53/SLC7A11 signaling pathway, potentially preventing the progression of PE.

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no2l通过p53/SLC7A11途径抑制子痫前期滋养细胞铁下垂。

背景：no2l在先兆子痫（PE）中下调。然而，NOC2L在PE发病中的潜在功能机制尚不清楚。方法：对缺氧刺激的HTR-8/SVneo细胞进行CCK-8、伤口愈合和Transwell试验，测定细胞活力、迁移和侵袭。GSH、MDA和Fe2+的水平用特定的商业试剂盒测定。通过C11-BODIPY染色测定脂质ROS水平。western blotting分析蛋白水平。此外，采用大鼠PE模型研究no2l对PE进展及相关铁下垂的影响。结果：no2l过表达可提高缺氧处理的滋养细胞活力，提高GSH、SLC7A11和GPX4水平，同时降低Fe2+、MDA和脂质ROS水平。此外，no2l过表达和铁抑素-1的应用都促进了滋养细胞的迁移和侵袭。相反，no2l敲低加重了缺氧诱导的铁下垂，抑制了细胞的迁移和侵袭能力。值得注意的是，PFT-α（一种p53抑制剂）可以消除no2l沉默对滋养细胞功能的影响。no2l过表达与大鼠胎儿血压和尿蛋白浓度的改善、胎盘病理损伤的减轻、死铁相关标志物的改变以及存活率的提高有关。结论：no2l通过p53/SLC7A11信号通路抑制滋养细胞铁下垂，可能阻止PE的进展。

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

Molecular and Cellular Endocrinology 医学-内分泌学与代谢

CiteScore

9.00

自引率

2.40%

发文量

174

审稿时长

42 days

期刊介绍： Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.