Maternal obesity impairs placental iron transport and ferroptosis pathways, reducing fetal iron accretion and programming persistent brain iron deficiency

Abstract Background: Maternal obesity is associated with fetal growth abnormalities and increased risk of adverse long-term offspring outcomes, yet the mechanisms linking maternal metabolic dysfunction to impaired development remain incompletely understood. Because fetal iron acquisition depends entirely on placental transport, we investigated whether maternal obesity disrupts placental iron handling and ferroptosis-associated pathways, thereby limiting fetal iron supply and altering offspring iron homeostasis. Methods: Female C57BL/6J mice were fed either a chow or high-fat high-sugar (HFHS) diet before and throughout pregnancy. Maternal, placental, fetal, and adult offspring iron status, tissue iron content, placental iron deposition, and expression of iron homeostasis- and ferroptosis-related genes were assessed. Placental transcriptomic analyses were integrated with developmental single-nucleus RNA sequencing datasets to define the cellular localization of iron transport and ferroptosis pathways. Results: Despite lower dietary iron intake, obese dams maintained normal systemic iron status. Maternal obesity reduced placental iron deposition, placental iron transport capacity, fetal circulating iron concentrations, placental weight, and fetal growth. These changes were accompanied by extensive remodeling of placental iron-regulatory pathways and a transcriptional shift toward increased ferroptosis susceptibility, including elevated Acsl4 and reduced expression of antioxidant and anti-ferroptotic genes. Developmental single-nucleus RNA sequencing identified syncytiotrophoblasts as the principal cellular hub coordinating placental iron transport and ferroptosis-associated pathways. Impaired placental iron handling was associated with markedly reduced fetal liver and brain iron accretion and tissue-specific transcriptional adaptations. Although systemic and hepatic iron homeostasis largely recovered in adulthood, offspring exposed to maternal obesity exhibited persistent brain iron deficiency and sustained alterations in cerebral ferroptosis-associated gene networks. Conclusions: Maternal obesity disrupts syncytiotrophoblast-mediated placental iron handling and promotes a pro-ferroptotic placental transcriptional environment, reducing fetal iron acquisition and contributing to fetal growth restriction. Persistent brain iron deficiency in adult offspring identifies impaired placental iron transport as a potential mechanism linking maternal obesity with long-term developmental programming.