1-nitropyrene triggers trophoblast dysfunction via EMPs-mediated ferroptosis through Glutathione peroxidase 4.

作者：Shuping Yu, Kai Wang, Yan Kang, Y. Mu, Zhenya Fang, Meihua Zhang, Shuxian Li · 发表于：Toxicology · 年份：2025 · DOI：10.1016/j.tox.2025.154190 · 被引用次数：2 · 研究领域：Medicine

1-Nitropyrene (1-NP), a prevalent environmental pollutant, poses significant risks to vascular and placental health. This study demonstrates that 1-NP induces vascular endothelial dysfunction by dose-dependently reducing human umbilical vein endothelial cell (HUVEC) viability, inhibiting proliferation, promoting apoptosis, and impairing tube formation. Notably, endothelial microparticles (EMPs) isolated from 1-NP-treated HUVECs (N-EMPs) exhibited distinct biological effects compared to control EMPs (C-EMPs). N-EMPs suppressed trophoblast viability, proliferation, invasion, and migration, correlating with N-cadherin downregulation and E-cadherin upregulation. Mechanistically, ferroptosis emerged as the primary driver of N-EMPs-induced trophoblast dysfunction, evidenced by reactive oxygen species (ROS) accumulation, glutathione depletion, elevated malondialdehyde and Fe²⁺ levels, and mitochondrial oxidative stress. Crucially, glutathione peroxidase 4 (GPX4) was identified as a central regulator, with its expression significantly downregulated by N-EMPs. Overexpression of GPX4 reversed ferroptosis markers (restoring GSH/SOD, reducing MDA/Fe²⁺) and rescued trophoblast viability, migration, and invasiveness. These findings establish a previously unrecognized pathogenic cascade wherein 1-NP triggers endothelial injury, releasing cytotoxic EMPs that propagate ferroptosis-dependent trophoblast dysfunction via GPX4 suppression. The central role of EMPs as mediators of environmental po...