Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction

Jiayu Xie; Hongzhu Lv; Xuanbei Liu; Zhennan Xia; Jiangwei Li; Enhui Hong; Boyun Ding; Wenying Zhang; Yizhao Chen

doi:10.1016/j.freeradbiomed.2023.02.015

Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction

Free Radic Biol Med. 2023 Apr:199:67-80. doi: 10.1016/j.freeradbiomed.2023.02.015. Epub 2023 Feb 18.

Authors

Jiayu Xie¹, Hongzhu Lv², Xuanbei Liu³, Zhennan Xia⁴, Jiangwei Li⁴, Enhui Hong³, Boyun Ding³, Wenying Zhang³, Yizhao Chen⁵

Affiliations

¹ Department of Neurosurgery, Zhujiang Hospital of Southern Medical University, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, 510282, China; Department of Neurosurgery, The First People's Hospital of Changde City of Xiangya Medical College of South Central University, Changde, 415000, China.
² Department of Neurosurgery, Zhujiang Hospital of Southern Medical University, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, 510282, China; Department of Neurosurgery, Dalian Municipal Central Hospital, Dalian, 116089, China.
³ Department of Neurosurgery, Zhujiang Hospital of Southern Medical University, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, 510282, China.
⁴ Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
⁵ Department of Neurosurgery, Zhujiang Hospital of Southern Medical University, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, 510282, China; Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China. Electronic address: YizhaoChen@126.com.

PMID: 36805044
DOI: 10.1016/j.freeradbiomed.2023.02.015

Abstract

Intracerebral hemorrhage (ICH) induces high mortality and disability. Neuronal death is the principal factor to unfavourable prognosis in ICH. However, the mechanisms underlying this association remain unclear. In this study, we investigated the molecular mechanisms by which neuronal ferroptosis occurs after ICH and whether the use of corresponding modulators can inhibit neuronal death and improve early outcomes in a rat ICH model. Our findings indicated that Nox4 and TF/TfR were upregulated in the perihematomal tissues of ICH rats. Oxidative stress and iron overload induced by Nox4 and TF/TfR promoted neuronal ferroptosis post-ICH. In contrast, application of Nox4-siRNA and the deferoxamine (DFO) attenuated peroxidation and iron deposition in the hemorrhagic brain, alleviated neuronal ferroptosis, and improved sensorimotor function in ICH rats. Additionally, our findings indicated that the post-ICH neuronal reduced glutathione (GSH) depletion were not related to dysfunctional glutamine delivery in astrocytes but rather to downregulation of EAAT3 due to lipid peroxidation-induced dysfunction in the neuronal membrane. These findings indicate that ferroptosis is involved in neuronal death in model rats with collagenase-induced ICH. Oxidative stress and iron overload induced by Nox4 and TF/TfR exacerbate ferroptosis after ICH, while Nox4 downregulation and iron chelation exert neuroprotective effects. The present results highlight the cysteine importer EAAT3 as a potential biomarker of ferroptosis and provide insight into the neuronal death process that occurs following ICH, which may aid in the development of translational treatment strategies for ICH.

Keywords: EAAT3; Ferroptosis; Intracerebral hemorrhage; Nox4; TF/TfR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death
Cerebral Hemorrhage / genetics
Ferroptosis* / genetics
Iron Overload* / genetics
NADPH Oxidase 4 / genetics
Oxidative Stress / physiology
Rats

Substances

NADPH Oxidase 4
Nox4 protein, rat
Slc1a1 protein, rat