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<p>Inhibition of ferroptosis was shown to alleviate pulmonary ischemia/reperfusion (I/R) injury. This study aimed to investigate the synergistic effects of bone marrow mesenchymal stem cells (BMSC)-derived exosomal METTL3 and Sevoflurane (Sev) in alleviating pulmonary I/R injury through ferroptosis regulation. In our study, pulmonary I/R injury models were established in mice and lung microvascular endothelial cells (LMECs). Commercial kits were used to measure myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and iron content. Lipid peroxidation was determined using the BODIPY 581/591 C11 probe by flow cytometry. Total m6A modification was measured by the commercial kit and m6A dot blot, while m6A modification of USP7 mRNA was analyzed by MeRIP and polysome profiling. The interaction between proteins or RNAs was analyzed by Co-IP, FISH combined with immunofluorescence, RNA pull-down, RIP, or dual-luciferase reporter assay. We proved Sev preconditioning mitigated ferroptosis in pulmonary I/R injury by activating the Nrf2 pathway. Co-treatment with BMSC-derived exosomes potentiated the protective effects of Sev by promoting USP7-mediated Nrf2 deubiquitination modification. Mechanistically, BMSC-derived exosomal METTL3 promoted USP7 mRNA translation through YTHDC2-dependent m6A modification. Also, METTL3 knockdown in exosomes suppressed the Nrf2 pathway and exacerbated ferroptosis, while METTL3 overexpression showed opposite effects. YTHDC2 knockdown abolished these protective effects caused by METTL3-overexpressed exosomes. In conclusion, BMSC-derived exosomal METTL3 reinforced the protective effects of Sev by promoting USP7 mRNA translation via YTHDC2-dependent m6A modification. Upregulated USP7 subsequently facilitated Nrf2 deubiquitination, thereby inhibiting ferroptosis and protecting against pulmonary I/R injury.</p>

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BMSC-derived exosomal METTL3 synergizes with Sevoflurane to inhibit ferroptosis in pulmonary ischemia/reperfusion injury by enhancing USP7 N6-methyladenosine modification

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Liang Zheng,
  • Xiang-yu Xie,
  • Kun Li,
  • Xiao-feng He,
  • Jiang Shen,
  • Cao Gao

摘要

Inhibition of ferroptosis was shown to alleviate pulmonary ischemia/reperfusion (I/R) injury. This study aimed to investigate the synergistic effects of bone marrow mesenchymal stem cells (BMSC)-derived exosomal METTL3 and Sevoflurane (Sev) in alleviating pulmonary I/R injury through ferroptosis regulation. In our study, pulmonary I/R injury models were established in mice and lung microvascular endothelial cells (LMECs). Commercial kits were used to measure myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and iron content. Lipid peroxidation was determined using the BODIPY 581/591 C11 probe by flow cytometry. Total m6A modification was measured by the commercial kit and m6A dot blot, while m6A modification of USP7 mRNA was analyzed by MeRIP and polysome profiling. The interaction between proteins or RNAs was analyzed by Co-IP, FISH combined with immunofluorescence, RNA pull-down, RIP, or dual-luciferase reporter assay. We proved Sev preconditioning mitigated ferroptosis in pulmonary I/R injury by activating the Nrf2 pathway. Co-treatment with BMSC-derived exosomes potentiated the protective effects of Sev by promoting USP7-mediated Nrf2 deubiquitination modification. Mechanistically, BMSC-derived exosomal METTL3 promoted USP7 mRNA translation through YTHDC2-dependent m6A modification. Also, METTL3 knockdown in exosomes suppressed the Nrf2 pathway and exacerbated ferroptosis, while METTL3 overexpression showed opposite effects. YTHDC2 knockdown abolished these protective effects caused by METTL3-overexpressed exosomes. In conclusion, BMSC-derived exosomal METTL3 reinforced the protective effects of Sev by promoting USP7 mRNA translation via YTHDC2-dependent m6A modification. Upregulated USP7 subsequently facilitated Nrf2 deubiquitination, thereby inhibiting ferroptosis and protecting against pulmonary I/R injury.