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Abstract Parkinson’s disease (PD) involves dysregulated mitophagy and immune responses, but the underlying mechanisms remain unclear. This study integrated single-cell sequencing (GSE157783) and Mendelian randomization (MR) to identify key mitophagy- and immune-related genes (MRGs/IRGs) in PD. We identified astrocyte and microglia subpopulations, screened differentially expressed genes (DEGs), and intersected them with strongly correlated IRGs-MRGs to prioritize candidates. MR analysis revealed four causal genes: SLC11A1 and DDX17 as protective factors, and MRAS and PDIA3 as risk factors. These genes were enriched in antigen processing and calcium signaling pathways, with dynamic expression patterns in glial differentiation. Bioinformatics predictions were validated in MPTP-induced PD mice, showing altered behavior and gene expression. Our findings highlight SLC11A1, DDX17, MRAS, and PDIA3 as therapeutic targets, bridging immune-mitophagy interactions in PD pathogenesis.
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