Both iron overload and ferroptosis induce trophoblast dysfunction and impair hCG secretion in cell models

Emerging evidence suggests that iron-related cell death may contribute to placental dysfunction. During pregnancy, placenta-mediated iron supply is critical for fetal development. Iron demand rises substantially during gestation and must be tightly regulated: while insufficient iron compromises fetal growth, excessive iron accumulation can be highly toxic. In particular, iron overload can trigger ferroptosis, an iron-dependent, non-apoptotic form of programmed cell death characterized by redox imbalance and accumulation of lipid-reactive oxygen species. In this study, we investigated ferroptosis and iron toxicity in various trophoblast cell models (BeWo, differentiated BeWo, and JEG-3). Treatment with ferroptosis inducers (erastin and RSL3) or iron (ammonium ferric citrate and hemin arginate) caused a significant, specific concentration-dependent reduction in hCG secretion, increased cytotoxicity, and oxidative stress. Iron chelator or antioxidant effectively reversed only some of these iron-induced effects. Here, we report that, in BeWo and JEG-3 choriocarcinoma cell models, iron overload and ferroptosis impair hCG secretion without affecting other endocrine functions. Further studies in primary trophoblasts and in vivo models are needed to determine whether these observations extend to placental function during pregnancy.