Identification of senescence‐related genes in Parkinson's disease reveals candidate therapeutic targets and pathological processes

BACKGROUND: Parkinson's disease (PD), a progressive neurodegenerative disease, is closely linked to the aging process; however, its precise molecular mechanisms remain unclear. This work aimed at clarifying the function of senescence-related genes (SRGs) in PD and investigating their molecular underpinnings, as well as their potential diagnostic and therapeutic significance. METHODS: By integrating bioinformatics with experimental validation, the CellAge database provided 278 SRGs for this study. A total of 2925 differentially expressed genes (DEGs) and 31 differentially expressed SRGs (DESRGs) were identified, which are mainly involved in signaling pathways, including nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and interleukin 17 (IL-17). Through protein-protein interaction (PPI) network analysis, 10 hub genes were identified, such as IRF7, IFNG, and BCL6. RESULTS: In PD mouse and MN9D cell models by D-galactose (D-gal) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), combined treatment (D-gal + MPTP) synergistically reduced tyrosine hydroxylase (TH) expression, promoted α-synuclein (α-syn) aggregation, aggravated cellular senescence, and caused significant upregulation of IRF7, whereas IRF7 small interfering RNA (siRNA) intervention reversed senescence- and PD-related pathological changes. Molecular docking analyses identified candidate small molecules targeting hub genes, including fostamatinib and ropsacitinib. In vitro experiments provided preliminary support that these compounds modulated SYK and TYK2 proteins and alleviated pathological phenotypes in cellular models. CONCLUSIONS: Overall, this study demonstrates that D-gal-induced aging-like stress accelerates PD-related pathological progression by activating multiple signaling pathways, including JAK-STAT, AGE-RAGE, and NF-κB, thereby promoting inflammation, oxidative stress, and neuronal dysfunction. Key genes including IRF7 may serve as candidate biomarkers, providing preliminary evidence for the role of senescence-like stress in PD pathogenesis.