The mTOR/AMPK signaling axis in placental dysfunction and preeclampsia: mechanisms and therapeutic targeting with metformin
Abstract
Preeclampsia continues to be one of the main causes of maternal and fetal complications in the absence of any effective treatment apart from placental expulsion. The present review presents a systematic evaluation of the involvement of mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) in preeclampsia through a discussion of mechanisms, pathophysiology, and clinical features, and explores the possible role of metformin as a therapeutic agent. In normal pregnancy, the physiological interaction between mTORC1 and AMPK enables appropriate trophoblast invasion and nutrition. However, in preeclampsia, chronic placental hypoxia and oxidative stress affect this delicate balance, resulting in a pathological situation characterized by increased AMPK activation and reduced mTORC1 activity, which adversely affects the function of trophoblasts and leads to increased anti-angiogenic factor production. However, the interaction is mutual because, while low doses of AMPK activation might restore metabolic equilibrium, higher doses, especially in combination with metformin, may further inhibit mTORC1. Thus, identifying the mTOR/AMPK axis as a key mechanism offers a new paradigm for understanding preeclampsia, yet therapeutic targeting with metformin requires careful titration to avoid aggravating the very imbalance it aims to correct. This nuanced perspective supports the future development of safe, placenta-directed therapies for preeclampsia.
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