Isorhynchophylline alleviates preeclampsia via PI3K/AKT/mTOR-mediated trophoblast oxidative stress inhibition

Preeclampsia (PE) is a severe pregnancy complication characterized by new-onset hypertension after 20 weeks of gestation, posing significant risks to maternal and fetal health. Placental ischemia-hypoxia-induced oxidative stress has been recognized as a central pathological mechanism underlying PE. Isorhynchophylline (IRN), a natural indole alkaloid, exhibits potent anti-inflammatory and antioxidant properties in multiple disease models. This study aims to systematically investigate the regulatory effects of IRN on oxidative stress in extravillous trophoblast (EVT) cells and elucidate its molecular mechanisms. In vitro experiments revealed that IRN markedly alleviated H₂O₂-induced oxidative stress injury in HTR-8 cells, primarily through the activation of the PI3K/AKT/mTOR signaling pathway. Specifically, IRN enhanced mitochondrial functions as evidenced by restoration of mitochondrial membrane potential, reduction in mitochondrial reactive oxygen species (ROS) levels, and an upregulation of mRNA expression of ATP6, CO1, and Cytb. Moreover, IRN inhibited the expression of apoptosis-related markers, underscoring its potent anti-apoptotic effects. In an L-NAME-induced PE rat model, IRN intervention effectively lowered maternal blood pressure, reduced proteinuria, and improved fetal survival rates. Collectively, this study reveals for the first time that IRN mitigates PE-associated pathological phenotypes by activating the PI3K/AKT/mTOR pathway, thereby ameliorating mitochondrial dysfunction and inhibiting oxidative stress and apoptosis in trophoblast cells. These findings provide critical theoretical support for the clinical translation of IRN as a potential therapeutic agent for PE.