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RXRγ attenuates cerebral ischemia–reperfusion induced ferroptosis in neurons in mice through transcriptionally promoting the expression of GPX4

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Abstract

Cerebral ischemia is a common cerebrovascular disease with high mortality and disability rate. Exploring its mechanism is essential for developing effective treatment for cerebral ischemia. Therefore, this study aims to explore the regulatory effect and mechanism of retinoid X receptor γ (RXRγ) on cerebral ischemia–reperfusion (I/R) injury. A mouse intraluminal middle cerebral artery occlusion model was established, and PC12 cells were exposed to anaerobic/reoxygenation (A/R) as an in vitro model in this study. Cerebral I/R surgery or A/R treatment induced ferroptosis, downregulated RXRγ and GPX4 (glutathione peroxidase 4) levels, upregulated cyclooxygenase-2 (COX-2) level and increased ROS (reactive oxygen species) level in A/R induced cells or I/R brain tissues in vivo or PC12 cells in vitro. Knockdown of RXRγ downregulated GPX4 and increased COX-2 and ROS levels in A/R induced cells. RXRγ overexpression has the opposite effect. GPX4 knockdown reversed the improvement of RXRγ overexpression on COX-2 downregulation, GPX4 upregulation and ferroptosis in PC12 cells. Furthermore, chromatin immunoprecipitation (ChIP) and luciferase reporter gene assays revealed that RXRγ bound to GPX4 promoter region and activated its transcription. Overexpression of RXRγ or GPX4 alleviated brain damage and inhibited ferroptosis in I/R mice. In conclusion, RXRγ-mediated transcriptional activation of GPX4 might inhibit ferroptosis during I/R-induced brain injury.

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Data availability statement

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

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Yanta District, Xi’an City, Shaanxi Province, 710061, People’s Republic of China

    Lei Yang & Maode Wang

  2. Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an City, Shaanxi Province, 710038, People’s Republic of China

    Lei Yang

  3. Second Department of Neurosurgery, Xinxiang Central Hospital, Xinxiang, Henan Province, 453003, People’s Republic of China

    Baoshun Du

  4. Department of Neurosurgery, Xi’an No.3 hospital, the Affiliated Hospital of Northwest University, Xi’an City, Shaanxi Province, 710018, People’s Republic of China

    Shitao Zhang

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  1. Lei Yang
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  2. Baoshun Du
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  3. Shitao Zhang
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  4. Maode Wang
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Contributions

LY performed experiments, collected data and drafted the manuscript. BD analyzed the data. SZ contributed the methodology. MW conceived and designed research. All authors read and approved the final manuscript.

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Correspondence to Maode Wang.

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Yang, L., Du, B., Zhang, S. et al. RXRγ attenuates cerebral ischemia–reperfusion induced ferroptosis in neurons in mice through transcriptionally promoting the expression of GPX4. Metab Brain Dis 37, 1351–1363 (2022). https://doi.org/10.1007/s11011-022-00988-5

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  • DOI: https://doi.org/10.1007/s11011-022-00988-5

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