OBJECTIVE: Type 1 interferon (IFN-I)-related genes play a critical role in Sjögren's syndrome (SS). However, study on its role and impact in peripheral blood B cells of SS is limited. This study investigated gene expression and epigenetic changes in IFI44L, analyzing its correlation with disease activity and clinical indicators. METHODS: Differentially expressed genes (DEGs) were identified from the GSE199868 dataset, while IFN-I-related genes were collected from GeneCards. Intersection analysis revealed IFN-I-related DEGs in SS. ClueGO, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, PPI network construction, and hub gene identification were conducted, with hub genes validated in GSE135809. Following this, we recruited 30 SS patients as the disease group and 11 healthy individuals as the control group. Clinical information and peripheral blood samples were collected from all participants. After isolating B cells from the peripheral blood, we used quantitative real-time polymerase chain reaction (RT-qPCR) and pyrosequencing to examine the mRNA expression and DNA methylation status of the IFI44L gene. Further analyses were conducted in conjunction with clinical indicators. RESULTS: GSE199868 analysis revealed 125 upregulated and 16 downregulated DEGs. Among 2794 IFN-I-related genes from GeneCards, 26 DEGs overlapped, enriched in viral genome replication and IFN-I pathways. 14 hub genes were identified, with 7 genes confirmed in GSE135809: ISG15, IFIT1, OASL, IFI6, RSAD2, IFI44L, and USP18. IFI44L mRNA expression was significantly higher in SS B cells ( CONCLUSION: The study highlights the clinical relevance of IFI44L mRNA expression and DNA hypomethylation in SS, underscoring its potential as a biomarker for disease activity and progression.