Schwann Cell‐Derived Extracellular Vesicles MFG ‐ E8 Alleviates Neuropathic Pain After Peripheral Nerve Injury Through Inhibiting Ferroptosis in Dorsal Root Ganglion Neurons by Regulating the PPARγ /p53/ SAT1 / ALOX15 Pathway

ABSTRACT The dorsal root ganglion (DRG) plays a critical role in mediating neuropathic pain (NP) following peripheral nerve injury (PNI), although the underlying mechanism remains unclear. This study investigated how Schwann cell (SCs)‐derived extracellular vesicles (SC‐EVs) regulate neuronal ferroptosis in NP after PNI. After validating isolated SCs (S‐100) and DRG neurons (NeuN), SC‐EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting for exosomal markers (Alix/CD9/CD63) and the absence of Calnexin. Co‐localization of PKH67 with β‐Tubulin‐III confirmed SC‐EVs uptake by DRG neurons. Biochemical assays and flow cytometry demonstrated SC‐EVs suppressed ferroptosis in both LPS‐stimulated DRG neurons and chronic constriction injury (CCI) rat models, while simultaneously inhibiting apoptosis, inflammation, and NP progression. Mechanistically, RT‐qPCR and western blotting revealed aberrant expression of PPARγ, p53, SAT1, and ALOX15 in LPS/CCI models. Co‐immunoprecipitation demonstrated that binding between PPARγ and p53 inhibits SAT1/ALOX15‐mediated ferroptosis in DRG neurons. Notably, SC‐EVs delivered MFG‐E8 to upregulate PPARγ and suppress the activation of the p53/SAT1/ALOX15, thereby attenuating neuronal ferroptosis and ameliorating CCI‐induced NP. In conclusion, MFG‐E8 delivered via SC‐EVs alleviates NP after PNI by modulating the PPARγ/p53/SAT1/ALOX15 signaling axis to inhibit CCI‐induced ferroptosis, offering novel therapeutic insights. image