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POU Domain Class 2 Transcription Factor 2 Inhibits Ferroptosis in Cerebral Ischemia Reperfusion Injury by Activating Sestrin2

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Abstract

Cerebral ischemia reperfusion injury (CIRI) is the commonest cause of brain dysfunction. Up-regulation of POU domain class 2 transcription factor 2 (POU2F2) has been reported in patients with cerebral ischemia, while the role of POU2F2 in CIRI remains elusive. Middle cerebral artery occlusion/reperfusion (MCAO/R) in mice and oxygen and glucose deprivation/reperfusion (OGD/R) in mouse primary cortical neurons were used as models of CIRI injury in vivo and in vitro. Lentivirus-mediated POU2F2 knockdown further impaired CIRI induced by MCAO/R in mice, which was accompanied by increased-neurological deficits, cerebral infarct volume and neuronal loss. Our evidence suggested that POU2F2 deficiency deteriorated oxidative stress and ferroptosis according to the phenomenon such as the abatement of SOD, GSH, glutathione peroxidase 4 (GPX4) activity and accumulation of ROS, lipid ROS, 4-hydroxynonenal (4-HNE) and MDA. In vivo, primary cortical neurons with POU2F2 knockdown also showed worse neuronal damage, oxidative stress and ferroptosis. Sestrin2 (Sesn2) was reported as a neuroprotection gene and involved in ferroptosis mechanism. Up-regulation of Sesn2 was observed in the ischemic penumbra and OGD/R-induced neuronal cells. Further, we proved that POU2F2, as a transcription factor, could bind to Sesn2 promoter and positively regulate its expression. Sesn2 overexpression relieved oxidative stress and ferroptosis induced by POU2F2 knockdown in OGD/R-treated neurons. This research demonstrated that CIRI induced a compensatory increase of POU2F2 and Sesn2. Down-regulated POU2F2 exacerbated CIRI through the acceleration of oxidative stress and ferroptosis possibly by decreasing Sesn2 expression, which offers new sights into therapeutic mechanisms for CIRI.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was supported by grants from the Youth Fund Project of National Natural Science Foundation of China (Grant Number 82001226) and the Natural Science Foundation of Jilin Province (Grant Number 20210101357JC).

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Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China

    **ghui Yang

  2. Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, **antai Street, Changchun, Jilin Province, China

    Qian Guo, Lu Wang & Shan Yu

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  1. **ghui Yang
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  2. Qian Guo
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  3. Lu Wang
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  4. Shan Yu
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Contributions

Conceptualization: JY, SY; methodology: JY, QG, LW, SY; writing—original draft preparation: JY; writing—review and editing: SY; funding acquisition: SY.

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Correspondence to Shan Yu.

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The animal experiment in this study was approved by the ethical guideline of the Animal Welfare and Research Ethics Committee of Jilin University.

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Yang, J., Guo, Q., Wang, L. et al. POU Domain Class 2 Transcription Factor 2 Inhibits Ferroptosis in Cerebral Ischemia Reperfusion Injury by Activating Sestrin2. Neurochem Res 48, 658–670 (2023). https://doi.org/10.1007/s11064-022-03791-x

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