Placental ferroptosis and impaired fetal growth in symptomatic and asymptomatic SARS-CoV-2 infections.

SARS-CoV-2 infection disrupts iron homeostasis in organs such as the lung. Emerging evidence suggests similar dysregulation in the placenta may impair function and fetal growth. Ferroptosis, an iron-dependent form of cell death, is driven by the accumulation of labile ferrous iron, catalyzing the peroxidation of polyunsaturated fatty acids in the absence of sufficient iron storage or antioxidant defenses. This pathway has been implicated in SARS-CoV-2-related tissue damage in other organs and may contribute to placental dysfunction during pregnancy. However, the influence of infection timing, symptom severity, and fetal sex on placental iron regulation remains unexamined. We analyzed placental samples from a cohort of SARS-CoV-2-exposed pregnancies in the first (n = 6), second (n = 14), or third trimester (n = 30), classified by symptom severity (asymptomatic n = 23, symptomatic n = 27) and fetal sex, alongside unexposed controls (n = 47). We assessed placental iron deposition, lipid peroxidation, and mRNA and protein expression of ferroptosis markers. Publicly available RNA-sequencing datasets from human placenta tissue, exposed or not to SARS-CoV-2, were analyzed to assess ferroptosis-related gene expression. SARS-CoV-2 infection, particularly in symptomatic cases, was associated with reduced placental weight and birth weight. Asymptomatic cases showed increased placental iron deposition, which correlated with lower birthweight and was accompanied by elevated expression of nuclear receptor coactivator 4, a cytosolic adaptor protein that mediates the selective autophagic degradation of ferritin (ferritinophagy) and iron release. Placentas from symptomatic patients exhibited evidence of altered iron transport and sex-specific down-regulation of antioxidant defenses. Transcriptomic analyses further suggested widespread disruption of ferroptosis pathways in placentas from infected patients. Our findings reveal that SARS-CoV-2 infection alters placental iron homeostasis and is associated with ferroptosis-related changes, with distinct molecular responses based on timing of infection, symptom severity, and fetal sex.