谷胱甘肽耗竭通过氧化应激激活cGAS-STING信号在子痫前期中的作用

Abstract

Oxidative stress can cause double-strand breaks in DNA in patients with preeclampsia (PE), but whether the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in PE remains unclear. Here, we show that glutathione (GSH) metabolism is disrupted in placentas from PE patients, leading to increased oxidative stress and activation of the cGAS-STING pathway. Using metabolomics and and CRISPR-Cas9 generated cGAS/STING knockout human trophoblast cells, we found that GSH depletion elevate reactive oxygen species (ROS) levels in HTR-8/SVneo cells, leading to cellular DNA damage and the release of double-stranded DNA (dsDNA) into the cytosol. This activates the cGAS-STING signalling, promoting NF-κB-mediated inflammatory and type I interferon responses. This mechanism highlights the critical role of ROS-mediated DNA damage and cGAS-STING-dependent inflammation in PE development, suggesting potential therapeutic targets for its intervention.