Su Fengyun, Shi Fanhua, Yang Chun, Zhao Fei, Geng Xiaolin, Yang Xiaojing, Zhao Xudong
Department of Pharmacy, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, 271000, Shandong Province, PR China.
Department of Obstetrics, Taian Maternal and Child Health Hospital, Tai'an, 271000, Shandong Province, PR China.
Mol Cell Endocrinol. 2025 Sep 15;607:112589. doi: 10.1016/j.mce.2025.112589. Epub 2025 Jun 4.
NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear.
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 Fe 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.
NOC2L overexpression increased the viability of hypoxia-treated trophoblast cells and increased the levels of GSH, SLC7A11, and GPX4 while simultaneously reducing Fe, 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.
NOC2L inhibits trophoblast ferroptosis through the p53/SLC7A11 signaling pathway, potentially preventing the progression of PE.
子痫前期（PE）中NOC2L表达下调。然而，NOC2L在PE发病机制中的潜在功能机制仍不清楚。
通过CCK-8、伤口愈合和Transwell实验检测缺氧刺激的HTR-8/SVneo细胞的细胞活力、迁移和侵袭能力。使用特定的商业试剂盒测量谷胱甘肽（GSH）、丙二醛（MDA）和铁（Fe）的水平。通过C11-硼二吡咯染色测定脂质活性氧（ROS）水平。通过蛋白质印迹分析蛋白质水平。此外，使用PE大鼠模型研究NOC2L对PE进展及相关铁死亡的影响。
NOC2L过表达增加了缺氧处理的滋养层细胞的活力，并提高了GSH、溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的水平，同时降低了Fe、MDA和脂质ROS水平。此外，NOC2L过表达和铁死亡抑制剂1（ferrostatin-1）的应用均促进了滋养层细胞的迁移和侵袭。相反，NOC2L敲低加剧了缺氧诱导的铁死亡增加，并抑制了细胞的迁移和侵袭能力。值得注意的是，p53抑制剂PFT-α处理消除了NOC2L沉默对滋养层细胞功能的影响。NOC2L过表达与血压和尿蛋白浓度改善、胎盘病理损伤减轻、铁死亡相关标志物改变以及大鼠胎儿存活率增加有关。
NOC2L通过p53/SLC7A11信号通路抑制滋养层细胞铁死亡，可能预防PE的进展。
