Identification and Validation of ISG20 as a Shared Immune-Related Crosstalk Marker in Rheumatoid Arthritis and Inflammatory Bowel Disease

Abstract

Purpose There is a bidirectional association between rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Patients with RA exhibit a higher prevalence of IBD, those with IBD are at a significantly increased risk of developing RA. The shared molecular mechanisms and key bridging molecules underlying remain to be explored. Methods Transcriptomic datasets from GEO were analyzed using WGCNA, differential expression, and immune-related genes to identify shared RA-IBD signatures. Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE), were employed to prioritize diagnostic markers. Single-cell RNA sequencing datasets were used to localize the cellular source of the hub gene. Subsequently, two independent large-scale peripheral blood datasets were retrieved to further provide transcriptomic profiles of circulating immune cells, serving as a “bridge” between RA and IBD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Findings were validated using collagen-induced arthritis (CIA) and dextran sulfate sodium (DSS) mice models, as well as in vitro TNF-α stimulation of MH7A and Caco-2 cells. Results Intersection analysis identified 19 core immune-driven genes shared between RA and IBD, both diseases are characterized by a highly activated immune profile, particularly T cell lineages. Among these, ISG20 emerged as a critical molecular link, exhibiting high diagnostic efficacy for RA and IBD. Single-cell transcriptomic analysis further revealed that ISG20 is predominantly expressed in T cell populations in both RA synovium and IBD colon. In peripheral blood datasets, 29 “bridge genes” were identified and found to be significantly enriched in chemokine signaling. Experimental validation confirmed that ISG20 mRNA levels were significantly upregulated in inflamed synovial tissues of CIA and colon of DSS mice, and in TNF-α-stimulated MH7A and Caco-2 cells. Conclusion ISG20 serves as a crosstalk molecular link across the RA and IBD. These findings provide molecular landscape for shared pathogenesis and diagnostic window for patients predisposed to the RA-IBD co-occurrence clinical phenotype.