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Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes

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Abstract

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis.

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Data Availability

The datasets generated in the current research are available from the corresponding author on reasonable request.

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Acknowledgements

The authors want to acknowledge the anonymous reviewers for their insightful comments to improve this paper. The authors are also thankful to Xiaoli Qu, from the State Key Laboratory for Manufacturing Systems Engineering of Xi’an Jiaotong University, for her assistance with image acquisition. And the authors would like to appreciate Dr. Yansong Li, Prof. Ning Huang, and Siyuan Lei for their helpful discussion on manuscript improvement.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81974540, 82274290), Key Research & Development Program of Shaanxi (Program No. 2022ZDLSF02-09), and Innovation Capability Support Program of Shaanxi (Program No. 2021TD-58).

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  1. Nan Wang and Yujing Zhao contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Nan Wang, Yujing Zhao, Meiyan Wu, Na Li, Chaoying Yan, Hongyan Guo, Qiao Li, Qing Li & Qiang Wang

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Contributions

Nan Wang: Conceptualization, Investigation, Validation, Data Curation, Investigation, Writing—Original Draft. Yujing Zhao: Methodology, Investigation, Validation, Formal analysis, Investigation. Meiyan Wu: Methodology, Investigation, Formal analysis, Visualization. Na Li: Software, Formal analysis, Data Curation. Chaoying Yan: Investigation, Visualization. Hongyan Guo: Software, Formal analysis. Qiao Li: Data Curation, Visualization. Qing Li: Visualization, Conceptualization, Writing—Review & Editing. Qiang Wang: Conceptualization, Writing—Review & Editing, Supervision, Project administration, Funding acquisition.

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Correspondence to Qing Li or Qiang Wang.

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Wang, N., Zhao, Y., Wu, M. et al. Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes. Mol Neurobiol 61, 1187–1201 (2024). https://doi.org/10.1007/s12035-023-03589-0

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