Placental Iron Homeostasis: Navigating the Delicate Balance Between Transport and Ferroptosis

As an essential micronutrient, iron plays a vital role in oxygen transport, deoxyribonucleic acid synthesis, and energy production and is a redox-active cofactor for many biological processes. However, ferrous iron (Fe²⁺) is toxic to cells because it reacts with hydrogen peroxide in the Fenton reaction to generate the hydroxyl (free) radical, a key player in oxidative stress, leading to lipid peroxidation and iron-dependent cell death (ferroptosis). Therefore, iron homeostasis is precisely regulated. Maintaining appropriate iron metabolism during pregnancy is a major challenge, as it requires adaptation at the level of the utero-placental-fetal unit to the dynamic changes in the demand for iron in the developing fetus during the later weeks of pregnancy. The distinction between physiological (normal) anemia, which results from hemodilution and leads to the depletion of intracellular iron stores (ferritin) in placental cells, and the manifestation of the toxic effects of iron overload and/or oxidative stress is not always clear. Moreover, chronic inflammation during pregnancy associated with increasingly common metabolic disorders such as obesity, diabetes and hypertension may induce ferroptosis. This review presents the current understanding of placental iron homeostasis and its disturbances, focusing on the role of ferroptosis in placental dysfunction. The rationale for potentially effective anti-ferroptotic treatment is also presented.