Targeting the GSK-3β/mTOR axis: a novel pharmacological strategy for preeclampsia prevention and treatment

Preeclampsia continues to be a primary contributor to maternal and perinatal morbidity, with no approved disease-modifying treatments. Recent evidence identifies the deregulation of the glycogen synthase kinase-3β (GSK-3β) and mechanistic target of rapamycin (mTOR) signaling pathway as a primary pathogenic factor in impaired placentation. This review suggests that pharmacological restoration of this axis constitutes a promising therapeutic approach for preeclampsia. We combine molecular pathogenesis with computational docking analyses to assess therapeutic candidates, including metformin, statins, tideglusib, and the mTOR activator MHY1485, that specifically regulate GSK-3β/mTOR activity. Our findings indicate that drugs like atorvastatin and tideglusib demonstrate a robust binding affinity for GSK-3β, whereas MHY1485 interacts with a regulatory pocket in mTOR, hence reinforcing their mechanistic potential. Conversely, late-stage vasodilatory therapies have proven ineffective clinically due to irreparable placental injury, highlighting the imperative for early, focused molecular intervention. We present the SWITCH Protocol, a precise preventive approach that integrates first-trimester biomarker screening with placenta-targeted medication. This study integrates structural insights, preclinical evidence, and translational trial design to establish GSK-3β/mTOR regulation as a fundamental pharmaceutical strategy for preeclampsia, transitioning the focus from symptomatic treatment to mechanism-based prevention.