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TRIM28 Fosters Microglia Ferroptosis via Autophagy Modulation to Enhance Neuropathic Pain and Neuroinflammation

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Abstract

This study explores the molecular underpinnings of neuropathic pain (NPP) and neuroinflammation, focusing on the role of TRIM28 in the regulation of autophagy and microglia ferroptosis. Leveraging transcriptomic data associated with NPP, we identified TRIM28 as a critical regulator of ferroptosis. Through comprehensive analysis, including Gene Ontology enrichment and protein-protein interaction network assessments, we unveiled GSK3B as a downstream target of TRIM28. Experimental validation confirmed the capacity of TRIM28 to suppress GSK3B expression and attenuate autophagic processes in microglia. We probed the consequences of autophagy and ferroptosis on microglia physiology, iron homeostasis, oxidative stress, and the release of proinflammatory cytokines. In a murine model, we validated the pivotal role of TRIM28 in NPP and neuroinflammation. Our analysis identified 20 ferroptosis regulatory factors associated with NPP, with TRIM28 emerging as a central orchestrator. Experimental evidence affirmed that TRIM28 governs microglial iron homeostasis and cell fate by downregulating GSK3B expression and modulating autophagy. Notably, autophagy was found to influence oxidative stress and proinflammatory cytokine release through the iron metabolism pathway, ultimately fueling neuroinflammation. In vivo experiments provided conclusive evidence of TRIM28-mediated pathways contributing to heightened pain sensitivity in neuroinflammatory states. The effect of TRIM28 on autophagy and microglia ferroptosis drives NPP and neuroinflammation. These findings offer promising avenues for identifying novel therapeutic targets to manage NPP and neuroinflammation.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

None.

Funding

This study was supported by The Sichuan Science and Technology Program (2023YFS0254), Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University (230006-01SZ), Sichuan Science and Technology Program (2021YJ0181), and Southwest Medical University School Program (2023QN005).

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Author notes

  1. Jian Tang and Qi Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, No. 25 Taiping Street, Luzhou, Sichuan, 646000, China

    Jian Tang, Qi Chen, Li Xiang, Ting Tu & Ying Zhang

  2. Department of Pain Management, The Affiliated Hospital, Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan, 646000, China

    Cehua Ou

  3. Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, 646000, China

    Ying Zhang

Authors
  1. Jian Tang
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  2. Qi Chen
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  3. Li Xiang
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  4. Ting Tu
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  5. Ying Zhang
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  6. Cehua Ou
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Contributions

JT, QC and LX wrote the paper and conceived and designed the experiments; TT and YZ analyzed the data; CHO collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

Corresponding authors

Correspondence to Ying Zhang or Cehua Ou.

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Ethics Approval

The Experimental Procedures and Animal Use Plans for this study were approved by the Animal Ethics Committee of the Affiliated Traditional Chinese Medicine Hospital (NO. 20220815- 004).

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Not applicable.

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Consent for publication was obtained from the participants.

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The author declares no conflict of interest.

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Tang, J., Chen, Q., Xiang, L. et al. TRIM28 Fosters Microglia Ferroptosis via Autophagy Modulation to Enhance Neuropathic Pain and Neuroinflammation. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04133-4

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