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Advanced Neurology

REVIEW ARTICLE
Ferroptosis in neonatal hypoxic-ischemic

brain injury and implications for therapeutic
development

1
Erin Cross 1 , Barbara Gundi 1 , Zhong-Ping Feng * , and Hong-Shuo Sun 1,2,3 *
1 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College
Circle, Toronto, ON, Canada
2 Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle,
Toronto, ON, Canada
3 Department of Pharmacology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College
Circle, Toronto, ON, Canada

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
*Corresponding authors: be studied. This review focuses on ferroptosis, a unique form of cell death, which was
Zhong-Ping Feng first described in 2012 and is characterized by iron-dependent lipid peroxidation,
(zp.feng@utoronto.ca)
Hong-Shuo Sun leading to lethal reactive oxygen species buildup. The role of ferroptosis in neonatal
(hss.sun@utoronto.ca) 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
Citation: Cross E, Gundi B,
–
Feng Z, Sun H. Ferroptosis factor erythroid 2-related factor 2, cystine/glutamate antiporter (system x ), and
c
in neonatal hypoxic-ischemic glutathione peroxidase-4, have been identified as key mediators of ferroptosis in
brain injury and implications for neonatal HIBI. In preliminary experiments, agents modulating the activity of these
therapeutic development. Adv
Neurol. 2025;4(1):25-39. and other targets effectively suppress ferroptosis and attenuate the structural and
doi: 10.36922/an.4575 functional consequences of neonatal HIBI. While considerable work is still required
Received: August 19, 2024 to establish the underlying mechanisms and therapeutic importance of these effects,
the foundational studies show that antiferroptotic agents may reduce the lasting
Revised: October 16, 2024 burden of neonatal HIBI and HIE.
Accepted: October 31, 2024
Published Online: December 12, Keywords: Hypoxic-ischemic brain injury; Hypoxic-ischemic encephalopathy; Neonatal
2024
brain injury; Ferroptosis; System x ; Glutathione peroxidase-4; Nuclear factor erythroid
–
Copyright: © 2024 Author(s). 2-related factor 2 c
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium, 1. Introduction
provided the original work is
properly cited. Neonatal hypoxic-ischemic brain injury (HIBI) involves inadequate blood and oxygen
Publisher’s Note: AccScience supply to the brain during birth, often resulting in hypoxic-ischemic encephalopathy
Publishing remains neutral with (HIE). HIE affects 1 – 8 in every 1,000 individuals born in high-income countries.
1
regard to jurisdictional claims in
published maps and institutional Affected neonates present with impaired reflexes, abnormal muscle tone, seizures,
affiliations. respiratory difficulties, and low heart rate. HIE carries a substantial risk of mortality
2,3
Volume 4 Issue 1 (2025) 25 doi: 10.36922/an.4575