CCR1-mediated monocyte chemotaxis in the immunopathology of primary Sjögren's syndrome: multi-omics integration analysis and computational target prioritization implicating

Objective: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease with no specific etiological treatment. Methods: Transcriptomic datasets (GSE51092, GSE66795; validation: GSE84844) and single-cell RNA sequencing data (GSE253568) were obtained from GEO. Network pharmacology screened active component targets of P. odoratum, and a "three-dimensional intersection" strategy identified candidate therapeutic targets. Single-cell analyses including monocyte subtyping, pseudotime trajectory, SCENIC transcription factor network, and CellChat cell communication analyses were performed. Molecular docking predicted drug-target binding, and RT-qPCR validated findings in clinical samples (pSS n = 65, HC n = 48). Results: CCR1 was the only candidate target simultaneously satisfying "drug-targetable, disease-related, and differentially expressed" conditions. CCR1 was significantly upregulated in pSS patients (AUC = 0.758, indicating moderate discriminatory capacity) and positively correlated with serum IgG levels (R = 0.49, P = 0.0057). Single-cell analysis demonstrated CCR1 was specifically highly expressed in classical monocytes (CD14++CD16-), with CCR1-positive monocytes significantly expanded in pSS (P = 0.0079). SCENIC analysis predicted STAT1 and EGR1 as candidate upstream transcription factors potentially associated with CCR1 expression. CellChat analysis predicted a potential "T/NK cell-derived CCL5-CCR1-mediated monocyte chemotactic recruitment" signaling axis. Moupinamide from P. odoratum showed predicted binding affinity with CCR1 (-8.1 kcal/mol). RT-qPCR confirmed elevated CCR1 expression in pSS PBMCs (P < 0.0001). Conclusions: This study provides exploratory multi-dimensional evidence consistent with a candidate role of CCR1 in pSS immunopathology. CCR1 is predominantly expressed in classical monocytes, predicted to be associated with STAT1/EGR1 regulatory activity, and computationally linked to monocyte recruitment through the CCL5-CCR1 chemotactic axis. Pseudotime analysis suggested a computational inference of monocyte differentiation trajectory differences associated with CCR1 expression dynamics, requiring experimental validation. Moupinamide from P. odoratum shows predicted binding affinity to CCR1, offering a computational hypothesis for the "yin-nourishing and dryness-moistening" therapeutic principle that warrants experimental validation.