The Emerging Roles of Ferroptosis in Neonatal Diseases

Abstract

Ferroptosis is a novel type of programmed cell death involved in many diseases' pathological processes. Ferroptosis is characterized by lipid peroxidation, reactive oxygen species accumulation, and iron metabolism disorder. Newborns are susceptible to ferroptosis due to their special physiological state, which is prone to abnormal iron metabolism and the accumulation of reactive oxygen species. Recent studies have linked ferroptosis to a variety of diseases in the neonatal period (including hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, and necrotizing enterocolitis). Ferroptosis may become an effective target for the treatment of neonatal-related diseases. In this review, the ferroptosis molecular mechanism, metabolism characteristics of iron and reactive oxygen species in infants, the relationship between ferroptosis and common infant disorders, and the treatment of infant diseases targeted for ferroptosis are systematically summarized.

Keywords: ferroptosis; iron metabolism; lipid peroxidation; neonatal disease; reactive oxygen species.

Figure 1

Mechanism of ferroptosis. PUFA became a part of the cell membrane under the action of ACSL4 and LPCAT3.Through the Fenton reaction and enzymatic reaction, PL-PUFA on the cell membrane undergoes a lipid peroxidation reaction to form PL-OOH. Due to the consumption of PL-PUFA and the toxic effect of peroxidation products, the cell membrane ruptures, eventually causing ferroptosis. Cystine enters the cytoplasm through System Xc- and rapidly transforms into cysteine to participate in GSH synthesis. GPX4 inhibits lipid peroxidation while reducing GSH to GSSG. Lipid peroxidation is also inhibited by FSP1 and DHODH on the cell membrane, which reduce CoQ10 to CoQ10H2. GCH1 can inhibit lipid peroxidation directly or indirectly. When the TF binds to the TFR on the cell membrane, it is endocytosed into the cell. Under the action of STEAP3 and DMT1, Fe2+ enters the cytoplasm and forms labile iron pools. Most Fe2+ is kept in ferritin. When intracellular iron is deficient, ferritin is transported to the lysosomes by NCOA4 to release Fe2+ through iron autophagy. Excess intracellular iron is excreted out of the cell through FPN1. When intracellular iron metabolism is imbalanced, the Fenton reaction and increased iron-containing enzyme activity cause ferroptosis.

Figure 2

Neonatal disease and ferroptosis. Newborns are easily exposed to oxidative stress environments such as hypoxia, hyperoxia, infection, inflammation, acidosis, and blood transfusion after birth, and their antioxidant capacity and iron metabolism capacity are poor, which will lead to increased ROS and free iron, and then cause ferroptosis through lipid peroxidation. A variety of neonatal diseases may be caused by ferroptosis, such as hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity.