Combined treatment with metformin and melatonin improves placental mitochondrial function via the AMPK/SIRT3 pathway in an LPS-induced model of preeclampsia

Background Preeclampsia (PE) is a severe hypertensive disorder in pregnancy, and disruption of placental energy homeostasis, particularly mitochondrial dysfunction, plays a critical role in its pathogenesis. Melatonin (MEL) and Metformin (MET), an effect associated through the AMP-activated protein kinase/Sirtuin 3 (AMPK/SIRT3) signaling pathway. However, the precise mechanisms remain unclear. Materials and methods The PE rat model was established in Sprague–Dawley (SD) rats by lipopolysaccharide (LPS) injection after confirmation of pregnancy. Pathological changes, protein expression, inflammatory and angiogenic factors, and mitochondrial status in placental tissue and HTR-8/SVneo trophoblasts were assessed by histology, immunohistochemistry, Western blotting, ELISA, RT-qPCR, reactive oxygen species (ROS) detection, transmission electron microscopy, and measurements of mitochondrial membrane potential and cytosolic calcium. Results Both MEL and MET individually activated the AMPK/SIRT3 signaling pathway, thereby enhancing mitochondrial function and placental energy homeostasis, while attenuating LPS-induced oxidative stress and inflammatory damage in placental tissue and trophoblast cells. Conclusions MEL and MET, when administered together, improve placental mitochondrial dysfunction and inflammatory injury in PE, which is associated with activation of the AMPK/SIRT3 signaling pathway, suggesting a potential therapeutic strategy for preeclampsia using clinically available agents.