Role of ferroptosis-related GPX4 signaling in the fusion of human trophoblast cells.

The placenta is mainly composed of trophoblast cells which fuse to create multinucleated syncytiotrophoblasts in the process of syncytialization. Syncytiotrophoblasts secrete human chorionic gonadotropin (hCG) for maintaining pregnancy. Impaired syncytialization contributes to pregnancy complications such as preterm labor and fetal growth restriction. Ferroptosis, a form of regulated non-apoptotic cell death, is characterized by the iron-dependent accumulation of lipid peroxides. This process is triggered by inactivation of glutathione peroxidase 4 (GPX4)-dependent antioxidant system. During pregnancy, iron demand increases, accompanied by elevated transferrin expression in syncytiotrophoblasts. However, the physiological relevance of ferroptosis signaling in trophoblast fusion remains largely explored. To address the impact of ferroptosis signaling on syncytialization, forskolin-stimulated trophoblast BeWo cells were treated with GPX4 inhibitors RSL3, ML-210, or erastin. Both RSL3 and ML-210 increased hCGβ expression and increased the number of fusogenic cells, alongside elevated intracellular Fe