Dong, x.; Wu, G.; Zhang, L.; Li, Q.; Li, Y.; Jin, F.; Li, R.; Ling, Y.; Xu, Y.

Parkinsons disease (PD) involves dysregulated mitophagy and immune responses, though the underlying mechanisms remain unclear. To identify key genes linking these pathways, we integrated single-cell RNA sequencing (GSE157783) with Mendelian randomization (MR) analysis, screening mitophagy-related genes (MRGs) and immune-related genes (IRGs). Differential expression analysis across PD cell subpopulations, combined with MR, revealed four causal genes: SLC11A1and DDX17 (protective) and MRAS and PDIA3 (risk). These genes were enriched in antigen presentation and calcium signaling pathways and exhibited dynamic expression in astrocytes and microglia during differentiation. Subsequent protein-protein interaction (PPI) network, regulatory (SCENIC), and drug-target analyses further characterized their roles. Validation in MPTP-induced PD mice confirmed behavioral deficits and altered expression of these genes, supporting their functional relevance. Our findings highlight SLC11A1, DDX17, MRAS, and PDIA3 as critical mitophagy-immune hubs in PD, offering mechanistic insights and therapeutic targets.