CD40LG as a Biomarker in Rheumatoid Arthritis: Links to Bone Destruction and Interstitial Lung Disease - A Bioinformatic Analysis With Clinical Validation.

Background and Aims: Biomarkers are essential tools in the diagnosis and management of various diseases. Rheumatoid arthritis (RA) is a systemic inflammatory disorder that frequently results in damage to joints and organs. Here, we examined potential biomarkers and therapeutic agents for RA patients. Methods: Three microarray datasets and clinical data for synovial tissue were sourced from the publicly available Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in RA versus osteoarthritis (OA) patients were identified, followed by functional enrichment analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network analysis to explore DEG-associated pathways and identify hub genes. Furthermore, serum levels of relevant antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, potential therapeutic compounds for RA were predicted using the Connectivity Map (CMap) database, and molecular docking was conducted to assess their binding affinities with target proteins. Results: A total of 409 DEGs were identified, with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analyses highlighting enrichment in cytokine activity, cytokine-receptor interactions, and the primary immunodeficiency pathway. Five key modules and hub genes were found using Cytoscape, and expression levels of CD40LG, ITGAX, and PTPRC were validated with another GEO data set. ELISA confirmed elevated serum CD40LG antibody levels in RA patients, suggesting its potential as a biomarker, especially in those with interstitial lung disease (ILD) or bone destruction. Connectivity map analysis identified small molecules that may reverse DEGs, and molecular docking showed emetine, oligomycin, cromoglicic acid, sulfinpyrazone, buspirone, and chlorogenic acid had favorable binding energies. Conclusion: CD40LG is a potential biomarker for RA, especially in patients with ILD or bone damage. Emetine, oligomycin, cromoglicic acid, sulfinpyrazone, buspirone, and chlorogenic acid are potential therapeutic agents for RA treatments.