Metformin ameliorates gestational diabetes mellitus via inhibiting ferroptosis of trophoblasts through the Nrf2/HO-1 signaling pathway.

Abstract

Both mothers and infants experience oxidative stress due to gestational diabetes mellitus (GDM), which is strongly associated with adverse pregnancy outcomes. Ferroptosis, a novel form of programmed cell death characterized by iron-dependent lipid peroxidation, is believed to play a critical role in the pathogenesis and progression of GDM. Metformin (MET) has shown potential in alleviating oxidative stress; however, research on its specific mechanisms of action in GDM remains limited. We collected placental tissues from GDM patients and healthy controls and established an in vitro GDM cell model. We measured markers of ferroptosis including malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase 4 (GPX4) activity. Additionally, we evaluated reactive oxygen species (ROS) levels, apoptosis, cell viability, and migration in the cell model. Our findings revealed significant changes in the GDM group compared to controls, including increased MDA and GSSG levels, decreased GSH levels, and reduced expression of GPX4 protein in the GDM placenta. High-glucose (HG) conditions were shown to reduce trophoblast cell viability and migration, accompanied by elevated ROS and MDA levels, as well as reduced expression of GSH, GPX4, Nrf2, and HO-1 proteins. Importantly, treatment with MET reversed these effects, similar to the action of deferoxamine mesylate (DFOM), a known ferroptosis inhibitor. These results confirm the occurrence of ferroptosis in the placentas of GDM patients and demonstrate that MET mitigates high-glucose-induced ferroptosis in trophoblasts through the Nrf2/HO-1 signaling pathway. This study provides novel insights into the protective mechanisms of MET, offering potential therapeutic strategies for GDM. management.