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

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

  • J Neurosci Res. 2023 Mar 16. doi: 10.1002/jnr.25184.
Xuying Tan 1,  Ting Zhang 2,  Xuejiao Ding 3,  Xiaopeng Zhao 2,  Qianjun Liu 1,  Zhenglong Xia 2,  Qihua Cao 1,  Feng Yan 4,  Li Chen 3,  Mingwei Zhu 3,  Yaping Tang 3,  Yanyan Song 1
Affiliations

Affiliations

  • 1 Department of Child Health Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
  • 2 Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
  • 3 Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
  • 4 Department of Delivery Room, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
PMID: 36929608 DOI: 10.1002/jnr.25184
Abstract

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.

Keywords

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.

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