miR-218a-5p derived from neural stem cell-exosomes inhibits ferroptosis in spinal cord injury through the Bmil/Mettl3/Alox12 axis

Ferroptosis is a pivotal pathogenic mechanism in spinal cord injury (SCI) for which effective therapeutic strategies are lacking. Neural stem cell-derived exosomes (NSC-exos) mitigate apoptosis and inflammation after SCI, but their role in ferroptosis remains unclear. This study explored how NSC-exos regulate ferroptosis using rat SCI and H₂O₂-induced PC12 cell injury models. NSCs were extracted, and NSC-exos were isolated/identified. RT-qPCR, Western blot, and functional assays (e.g., cell apoptosis, LDH, MDA, ROS, mitochondrial function) evaluated ferroptosis markers. Rat motor function and neuronal survival were assessed, and molecular assays including knockdown, overexpression, and rescue experiments tested interactions among miR-218a-5p, Bmi1, Mettl3, and Alox12. Results showed NSC-exos reduced H₂O₂-induced PC12 cell injury and oxidative stress. NSC-exos-derived miR-218a-5p inhibited ferroptosis by targeting Bmi1, promoting Mettl3 ubiquitination/degradation. Reduced Mettl3 decreased Alox12 mRNA m⁶A methylation (via YTHDF2), suppressing Alox12 protein expression. Critically, overexpression of Bmi1 or Alox12 partially reversed the anti-ferroptotic effects of miR-218a-5p mimic or NSC-exos, supporting a linear causal pathway. Thus, NSC-exos miR-218a-5p degrades Mettl3 via Bmi1 to downregulate Alox12, inhibiting ferroptosis and alleviating SCI.