Ferroptosis in neonatal hypoxic-ischemic brain injury and implications for therapeutic development

Abstract

The morbidity and mortality associated with neonatal hypoxic-ischemic brain injury (HIBI) and the related clinical syndrome, hypoxic-ischemic encephalopathy (HIE), remain substantial. Consequently, treatment alternatives to therapeutic hypothermia, the current standard of care, are urgently needed. Therefore, unique aspects of the complex mechanistic underpinnings of neonatal HIBI and HIE must be studied. This review focuses on ferroptosis, a unique form of cell death, which was first described in 2012 and is characterized by iron-dependent lipid peroxidation, leading to lethal reactive oxygen species buildup. The role of ferroptosis in neonatal HIBI has been indirectly supported by decades of research and directly demonstrated using in vivo and in vitro models in recent years. Molecular targets, including nuclear factor erythroid 2-related factor 2, cystine/glutamate antiporter (system x_c^-), and glutathione peroxidase-4, have been identified as key mediators of ferroptosis in neonatal HIBI. In preliminary experiments, agents modulating the activity of these and other targets effectively suppress ferroptosis and attenuate the structural and functional consequences of neonatal HIBI. While considerable work is still required to establish the underlying mechanisms and therapeutic importance of these effects, the foundational studies show that antiferroptotic agents may reduce the lasting burden of neonatal HIBI and HIE.

Graphical abstract

Keywords

Hypoxic-ischemic brain injury / Hypoxic-ischemic encephalopathy / Neonatal brain injury / Ferroptosis / System x_c^- / Glutathione peroxidase-4 / Nuclear factor erythroid 2-related factor 2

Funding

None.

Conflict of interest

Zhong-Ping Feng and Hong-Shuo Sun are Editorial Board Members of this journal but were not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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