Oxidative stress is considered a key hallmark of preeclampsia, which causes the dysregulation of trophoblast cells, and it contributes to the pathogenesis of preeclampsia. Emerging evidence has suggested bromodomain-containing protein 4 (BRD4) as a key regulator of oxidative stress in multiple cell types. However, whether BRD4 participates in regulating oxidative stress in trophoblast cells remains undetermined. The current study was designed to explore the potential function of BRD4 in the regulation of oxidative stress in trophoblast cells. Our data revealed that BRD4 expression was elevated in trophoblast cells stimulated with hydrogen peroxide. Exposure to hydrogen peroxide caused marked decreases in the levels of proliferation and invasion but promoted apoptosis and the production of ROS in trophoblast cells. Knockdown of BRD4, or treatment with a BRD4 inhibitor, markedly increased the levels of cell proliferation and invasion and decreased apoptosis and ROS production following the hydrogen peroxide challenge. Further data indicated that suppression of BRD4 markedly decreased the expression levels of Keap1, but increased the nuclear expression of Nrf2 and enhanced Nrf2-mediated transcriptional activity. BRD4 inhibition-mediated protective effects were markedly reversed by Keap1 overexpression or Nrf2 inhibition. Overall, these results demonstrated that BRD4 inhibition attenuated hydrogen peroxide-induced oxidative stress injury in trophoblast cells by enhancing Nrf2 activation via the downregulation of Keap1. Our study highlights the potential importance of the BRD4/Keap1/Nrf2 axis in the modulation of the oxidative stress response in trophoblast cells. Targeted inhibition of BRD4 may offer new opportunities for the development of innovative therapeutic approaches to treat preeclampsia.

氧化应激被认为是先兆子痫的关键标志，它会导致滋养层细胞失调，并有助于先兆子痫的发病机制。新出现的证据表明，含溴结构域蛋白 4 (BRD4) 是多种细胞类型氧化应激的关键调节剂。然而，BRD4 是否参与调节滋养层细胞的氧化应激尚不清楚。目前的研究旨在探索 BRD4 在调节滋养层细胞氧化应激中的潜在功能。我们的数据显示，在过氧化氢刺激的滋养层细胞中，BRD4 表达升高。暴露于过氧化氢导致增殖和侵袭水平显着降低，但促进滋养细胞凋亡和 ROS 的产生。BRD4 的击倒，或用 BRD4 抑制剂治疗，显着增加细胞增殖和侵袭的水平，并减少过氧化氢攻击后的细胞凋亡和 ROS 产生。进一步的数据表明，BRD4 的抑制显着降低了 Keap1 的表达水平，但增加了 Nrf2 的核表达并增强了 Nrf2 介导的转录活性。Keap1 过表达或 Nrf2 抑制显着逆转 BRD4 抑制介导的保护作用。总体而言，这些结果表明，BRD4 抑制通过下调 Keap1 增强 Nrf2 活化来减轻过氧化氢诱导的滋养层细胞氧化应激损伤。我们的研究强调了 BRD4/Keap1/Nrf2 轴在调节滋养层细胞氧化应激反应中的潜在重要性。