Placental trophoblasts exhibit iron dysregulation and ferroptosis signaling associated with SARS-CoV-2 restriction.

Prenatal SARS-CoV-2 infection is associated with adverse pregnancy outcomes, but mechanisms shaping placental viral spread and injury remain unclear. We show that SARS-CoV-2 induces ferroptosis-linked iron dysregulation in the placenta as a potential attempt to limit trophoblast infection. Placentas from early gestation infection exhibit persistent viral protein expression, iron accumulation, disrupted iron transport protein localization, and reduced expression of the ferroptosis inhibitor glutathione peroxidase 4 (GPX4) at term. In trophoblast cells and stem cell-derived trophoblast organoids with apical-out polarity, SARS-CoV-2 Delta infection suppresses the iron efflux transporter ferroportin and ferroptosis inhibitors GPX4 and phospholipase A2 group VI (PLA2G6), promoting ferroptotic signaling. Pharmacological activation of ferroptosis reduces viral titers in trophoblasts, supporting a potential antiviral role during infection. Together, these findings identify a possible mechanism through which the placenta restricts SARS-CoV-2 levels. However, this response is accompanied by placental iron sequestration that may compromise maternal-fetal iron transfer, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage.