CASP1 as a potential target of Dendrobium in Sjögren's syndrome: Multi-omics analysis and preliminary experimental evidence.

OBJECTIVE: Primary Sjögren's Syndrome (pSS) is an autoimmune disorder currently lacking effective therapeutic treatments. This study aims to explore the potential role of CASP1 in the pathogenesis of pSS and the possible therapeutic mechanisms of the traditional Chinese medicine component, Dendrobium, through multi-omics integrative analysis.

METHODS: We employed a multi-level integrative analysis strategy. First, differential expression analysis was conducted independently on three transcriptomic datasets derived from the parotid gland (GSE40611), salivary gland (GSE143153), and whole blood (GSE66795). Meta-analysis was then performed to identify differentially expressed genes that were consistently present across tissues. Next, using network pharmacology, we screened for the active components of Dendrobium from the HERB 2.0 database and predicted their potential targets. The intersection of these targets with disease-related genes and differentially expressed genes was analyzed to identify core therapeutic targets. Finally, we performed multi-dimensional validation using an independent validation cohort from whole blood (GSE84844), peripheral blood single-cell sequencing data (GSE214974), molecular docking, and RT-qPCR on clinical samples to validate the clinical significance, cellular sources, immune mechanisms, and drug-binding potential of the core targets.

RESULTS: Meta-analysis identified 293 differentially expressed genes that were stably present in pSS patients. Through a three-way intersection analysis of drug targets, disease genes, and differentially expressed genes, we identified three core candidate genes: CASP1, HSP90AA1, and RPS6KA1. In subsequent multi-dimensional validation, CASP1 exhibited the most prominent clinical potential: it was significantly upregulated in the independent validation cohort and demonstrated excellent diagnostic performance (AUC = 0.920), with expression levels positively correlated with IgA and IgM. Single-cell sequencing analysis confirmed that CASP1 was specifically highly expressed in monocytes and dendritic cells in the peripheral blood of pSS patients. Mechanistically, the high expression of CASP1 was closely related to the activation of innate immune pathways such as Toll-like receptors and the formation of a pro-inflammatory immune microenvironment. Molecular docking simulations indicated that the key active component of Dendrobium, 6-hydroxy-dendrobine, exhibited good binding potential with the CASP1 protein. Finally, RT-qPCR confirmed that CASP1 mRNA expression was significantly higher in the peripheral blood mononuclear cells of 65 pSS patients compared to healthy controls (p < 0.001).

CONCLUSION: Through bioinformatics analysis and preliminary experimental validation, this study suggests that CASP1 may be involved in the immunopathological process of pSS, providing a potential molecular target for Dendrobium-based therapy for pSS. These findings provide a theoretical foundation for developing CASP1-based therapeutic strategies for pSS, revealing a potential mechanism through computational predictions. However, causal relationships and therapeutic effects need further functional validation studies.