Iron overload facilitates neonatal hypoxic-ischemic brain damage via SLC7A11-mediated ferroptosis

Oxidative damage and cell death are involved in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Ferroptosis is a newly identified mode of cell death that results from the oxidative damage induced by excessive iron. In HIBD, iron accumulates in brain tissues due to the massive destruction of red blood cells and increased permeability of the blood brain barrier vasculature, which can trigger Ferroptosis. Ferroptosis is implicated in various diseases involving neuronal injury; however, the roles of iron and Ferroptosis in HIBD have not been identified. In the present study, we investigated the role of iron overload in neuronal Ferroptosis both in HIBD rat models and in oxygen- and glucose-deprived (OGD) SH-SY5Y cells. We observed that iron deposition in the cerebral cortex was significantly increased in HIBD rats. Features of Ferroptosis such as shrunken mitochondria, increased MDA (malondialdehyde) levels, and reduced solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) expression were observed in the cerebral cortex of HIBD rats. Administration of an iron chelator in HIBD rats upregulated SLC7A11 expression and alleviated neuronal Ferroptosis in cerebral cortex tissue. Additionally, overexpression of SLC7A11 in SH-SY5Y cells increased cell viability and attenuated OGD-induced Ferroptosis. Our results demonstrate that iron overload induces neuronal Ferroptosis by inhibiting SLC7A11 expression in HIBD. Inhibition of neuronal Ferroptosis may be a promising strategy to alleviate brain damage in HIBD.

RRID:AB_1097390; RRID:AB_11129865; RRID:AB_1310222; RRID:AB_2302075; RRID:AB_2722749; RRID:AB_2890944; RRID:AB_2904534; RRID:CVCL_0019; RRID:SCR_000011; RRID:SCR_002140; RRID:SCR_002798; RRID:SCR_003070; RRID:SCR_013673; RRID:SCR_014320; RRID:SCR_015040; RRID:SCR_015572; RRID:SCR_015804; RRID:SCR_019096; RRID:SCR_019378; RRID:SCR_019443; RRID:SCR_019749; RRID:SCR_020153; RRID:SCR_020245; RRID:SCR_020530; RRID:SCR_021693; ferroptosis; iron overload; lipid peroxidation; neonatal hypoxic-ischemic brain damage; solute carrier family 7 member 11.