Iron-mediated oxidative cell death is a potential contributor to neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia

The review article discusses current knowledge of iron-mediated oxidative cell death (ferroptosis) and its potential role in the pathogenesis of neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia. The connection between metabolic conditions related to hemolysis (iron and bilirubin overload) and iron-induced lipid peroxidation is highlighted. Neurotoxicity of iron and bilirubin is associated with their release from destructed erythrocytes in response to hemolytic disease. Iron overload initiates lipid peroxidation through the reactive oxygen species production resulting to oxidative damage to cells. Excessive loading of immature brain cells by iron-induced formation of reactive oxygen species contributes to the development of various neurodevelopmental disorders. The causal relationship between iron overload and susceptibility of brain cells to oxidative damage by ferroptosis appears to be associated not only with the amount of redox-active iron involved in oxidative cell damage but also with the degree of maturity of the neonatal brain. Neuronal dysfunction induced by neonatal hemolytic disease can represent a specific model of ferroptosis. The mechanism by which iron overload triggers ferroptosis is not completely explained. However, hemolysis of neonatal red blood cells appears to be a determining factor. Potential therapeutic strategy with iron-chelating agents to inhibit ferroptosis has a promising future in postnatal care.