Preeclampsia (PE) is a high-prevalence pregnancy disease characterized by placental insufficiency, gestational hypertension, and proteinuria. Overexpression of the A isoform of the STOX1 transcription factor (STOX1A) recapitulates PE in mice, and STOX1A overexpressing trophoblasts recapitulate PE patients hallmarks in terms of gene expression and pathophysiology. STOX1 overexpression induces nitroso-redox imbalance and mitochondrial hyper-activation. Here, by a thorough analysis on cell models, we show that STOX1 overexpression in trophoblasts alters inducible nitric oxide synthase (iNOS), nitric oxide (NO) content, the nitroso-redox balance, the antioxidant defense, and mitochondrial function. This is accompanied by specific alterations of the Krebs cycle leading to reduced l-malate content. By increasing NOS coupling using the metabolite tetrahydrobiopterin (BH4) we restore this multi-step pathway in vitro. Moving in vivo on two different rodent models (STOX1 mice and RUPP rats, alike early onset and late onset preeclampsia, respectively), we show by transcriptomics that BH4 directly reverts STOX1-deregulated gene expression including glutathione metabolism, oxidative phosphorylation, cholesterol metabolism, inflammation, lipoprotein metabolism and platelet activation, successfully treating placental hypotrophy, gestational hypertension, proteinuria and heart hypertrophy. In the RUPP rats we show that the major fetal issue of preeclampsia, Intra Uterine Growth Restriction (IUGR), is efficiently corrected. Our work posits on solid bases BH4 as a novel potential therapy for preeclampsia.

先兆子痫（PE）是一种高发妊娠疾病，其特征是胎盘功能不全、妊娠期高血压和蛋白尿。STOX1 转录因子 A 亚型 (STOX1A) 的过度表达再现了小鼠中的 PE，而 STOX1A 过度表达的滋养层则再现了 PE 患者在基因表达和病理生理学方面的特征。STOX1 过度表达会诱导亚硝基氧化还原失衡和线粒体过度激活。在这里，通过对细胞模型的全面分析，我们发现滋养层中 STOX1 的过度表达会改变诱导型一氧化氮合酶 (iNOS)、一氧化氮 (NO) 含量、亚硝基氧化还原平衡、抗氧化防御和线粒体功能。这伴随着克雷布斯循环的特定改变，导致l-苹果酸含量减少。通过使用代谢物四氢生物蝶呤 (BH4) 增加 NOS 偶联，我们在体外恢复了这种多步骤途径。在两种不同的啮齿动物模型（STOX1 小鼠和 RUPP 大鼠，分别为早发型和晚发型先兆子痫）上进行体内实验，我们通过转录组学表明 BH4 直接恢复 STOX1 失调的基因表达，包括谷胱甘肽代谢、氧化磷酸化、胆固醇代谢、炎症、脂蛋白代谢和血小板活化，成功治疗胎盘营养不良、妊娠期高血压、蛋白尿和心脏肥大。在 RUPP 大鼠中，我们发现先兆子痫的主要胎儿问题，即子宫内生长受限（IUGR）已得到有效纠正。我们的工作将固体碱 BH4 视为一种治疗先兆子痫的新型潜在疗法。