ObjectiveTo investigate the molecular mechanisms by which the receptor for advanced glycation end products（RAGE）-signal transducer and activator of transcription 3（STAT3） signaling pathway mediates mitochondrial injury in striosome/matrix compartment neurons under dopaminergic depletion in Parkinson's disease （PD）. MethodsA 6-hydroxydopamine （6-OHDA）-induced rat model of PD was established and treated with the RAGE inhibitor FPS-ZM1. Immunohistochemistry， double immunofluorescence staining， transmission electron microscopy （TEM）， Western blotting， and quantitative real-time PCR （qRT-PCR） were performed to evaluate RAGE and STAT3 expression as well as mitochondrial ultrastructure alterations in the striosome/matrix compartment. ResultsThe density of RAGE-positive structures and the protein expression level of RAGE in the striosome/matrix compartment were significantly increased in PD rats compared with controls （P<0.05）. Immunohistochemical and double immunofluorescence analyses demonstrated widespread STAT3 expression in striatal neurons， while the number of NeuN/STAT3 double-positive cells was significantly elevated in the PD group （P<0.05）. Western blotting and qRT-PCR further confirmed significant upregulation of STAT3 protein and mRNA expression in PD rats （P<0.05）. TEM analysis revealed marked mitochondrial abnormalities in PD neurons， including reduced mitochondrial density， enlarged mitochondrial area， decreased cristae number， cristae membrane disruption， and outer membrane damage （all P<0.05）. Notably， FPS-ZM1 treatment partially reversed these mitochondrial ultrastructural alterations. ConclusionActivation of the RAGE-STAT3 signaling pathway contributes to mitochondrial structural disruption in striosome/matrix compartment neurons in PD. These findings suggest that the striosome/matrix compartment may represent a novel pathological target for investigating mitochondrial dysfunction and neurodegeneration in PD.