A neuron-distributed DEK integrates ac4C modification and neuroinflammation in pathogenesis of Parkinson disease: evidence from Mendelian randomization, multi-omics and

Background: Epi-transcriptomic modifications, particularly N4-acetylcytidine (ac4C), and chronic neuroinflammation have emerged as pivotal players in the pathogenesis of Parkinson's disease (PD). However, the specific molecular co-expression patterns linking ac4C RNA modification to neuronal inflammatory responses remains largely uncharted. Objective: This study aimed to decode the ac4C-neuroinflammation (AN)-associated molecular patterns in PD and to identify a neuron-specific central pathogenic and therapeutic factor. Methods: We integrated multi-omics analyses by using peripheral blood bulk transcriptomes (GSE18838, GSE49126, GSE22491, GSE6613, and GSE57475) and GWAS data from PD patients for identification of AN-related risk genes. Next, consensus clustering and 3 machine learning algorithms (LASSO, RF, and SVM-RFE) were applied for patient stratification, hub gene identification, and diagnostic modeling. Single-cell transcriptomic profiling of PD patients (GSE140231) was leveraged to map the cellular distribution and mechanistic roles of the hub gene within the substantia nigra (SN). An AI-driven active learning framework and the CTD database were utilized to screen therapeutic candidates targeting the hub gene, with binding affinities validated via molecular docking. Results: We pinpointed 7 AN-associated risk DEGs for PD patients, including HSP90AA1, DEK, LEF1, IRF2, BCL2L1, CFL1, and BCR, which effectively stratified PD patients into 2 distinct immune-molecular subgroups. DEK can be considered as neuron-distributed and up-regulated AN-associated central pathogenic factor for PD patients. The DrugReflector active learning framework identified BRD-K57589644 as a computationally prioritized compound warranting further investigation. Conclusion: This study establishes a novel AN-associated molecular patterns in PD, identifying DEK as a computationally identified neuron-specific factor associated with ac4C modification and neuroinflammatory cascades for PD patients.