〔Abstract〕 Objective To systematically screen and validate key immunogenic cell death (ICD)-related genes that play important roles in primary sjögren’s syndrome (pSS) using multi-omics data. MethodsGene expression profiles of pSS patients and healthy controls (GSE66795, 131pSS patients/29 healthy controls) were obtained from the Gene Expression Omnibus (GEO) database. Candidate genes were selected by intersecting these profiles with known ICD core gene sets and pSS-related targets. The CIBERSORT algorithm was used to analyze immune cell infiltration characteristics. Validation of gene expression was performed using transcriptomic data from sorted CD8 + T cell subsets (GSE93683). Finally, labial gland tissues and peripheral blood samples from 10 pSS patients and 4 healthy controls were collected, and key genes were experimentally validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). ResultsSeven intersecting genes from the ICD-differentially expressed genes (DEGs)-pSS intersection were identified [caspase 1 ( CASP1), forkhead box P3 ( FOXP3), interferon-gamma ( IFNG), myeloid differentiation primary response 88 ( MYD88), toll-like receptor 7 ( TLR7), DExD/H-box helicase 58 ( DDX58), and interferon induced helicase C domain 1 ( IFIH1)]. Immune infiltration analysis showed that in pSS labial gland tissues, the proportions of naïve B cells and dendritic cells significantly increased, while the proportions of resting NK cells and M0 macrophages decreased ( P<0.05). Transcriptomic data of CD8 +T cell subsets indicated that IFIH1 expression was significantly elevated in central memory CD8 +T cells ( P<0.05). RT-qPCR experimental validation revealed that DDX58, IFIH1, and CASP1 were significantly upregulated in both peripheral blood leukocytes and labial gland tissues of pSS patients (all P<0.05), whereas IFNG expression increased in peripheral blood but decreased in labial gland tissues ( P<0.05). Conclusion This study identified and confirmed DDX58, IFIH1, CASP1, and IFNG as key ICD-related genes in pSS through a combination of bioinformatics and experimental validation, providing new candidate targets for further understanding the immunopathological mechanisms of pSS.