• Junjie Dong, Zhiqiang Gong, Hangchuan Bi, Jin Yang, Bing Wang, Kaili Du, Chunqiang Zhang, and Lingqiang Chen.
• Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
• Neuroscience. 2024 Sep 25; 556: 738573-85.

ObjectiveThe aim of this study was to investigate the molecular mechanism of exosomal miR-219-5p derived from bone marrow mesenchymal stem cells (BMSCs) in the treatment of spinal cord injury (SCI).MethodsBasso Beattie Bresnahan (BBB) score and tissue staining were used to assess SCI and neuronal survival in rats. The contents of Fe2+, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were detected by a kit. The expression levels of ubiquitin-conjugating enzyme E2 Z (UBE2Z), nuclear factor erythroid 2-related Factor 2 (NRF2) and ferroptosis-related proteins were detected by Western blotting. In addition, the ability of BMSC-derived exosomes to inhibit ferroptosis in neuronal cells in rats with SCI was validated by in vivo injection of ferroptosis inhibitors/inducers.ResultsIn this study, we found that miR-219-5p-rich BMSC-derived exosomes inhibited ferroptosis in SCI rats and that the alleviating effect of BMSC-Exos on SCI was achieved by inhibiting the ferroptosis signaling pathway and that NRF2 played a key role in this process. Our study confirmed that BMSC exosome-specific delivery of miR-219-5p can target UBE2Z to regulate its stability and that overexpression of UBE2Z reverses miR-219-5p regulation of NRF2. In addition, in vivo experiments showed that BMSC exosomes alleviated ferroptosis in neuronal SCI progression, and inhibiting the expression of miR-219-5p in BMSCs reduced the alleviating effect of exosomes on ferroptosis in neuronal cells and SCI.ConclusionmiR-219-5p in BMSC-derived exosomes can repair the injured spinal cord. In addition, miR-219-5p alleviates ferroptosis in neuronal cells induced by SCI through the UBE2Z/NRF2 pathway.Copyright © 2024. Published by Elsevier Inc.

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