Identifying therapeutic target genes for rheumatoid arthritis-associated interstitial lung disease by systematic druggable genome-wide Mendelian randomization analysis.

Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality rates in patients with rheumatoid arthritis (RA). Currently, the treatment of RA-ILD remains highly challenging. This study aims to identify potential therapeutic targets for RA-ILD through a systematic druggable genome-wide Mendelian randomization (MR) analysis. We performed a genome-wide MR analysis by integrating expression quantitative trait loci (eQLT) of 6888 druggable genes and genetic summary statistics from a genome-wide association study of RA-ILD. A colocalization analysis was performed to prioritize genes strongly associated with RA-ILD. Enrichment analysis, protein-protein interaction network construction, drug prediction, and molecular docking were further conducted to provide valuable guidance for the development of targeted therapies. A total of 33 druggable genes showed significant association with RA-ILD, one of which, CISD1, was robustly validated through colocalization analysis. Notably, three key target genes-CST7, ATN1, and FCER2-were identified as potential mediators of the treatment effect of cyclophosphamide, a current clinical treatment for RA-ILD. This study employed MR and colocalization analysis to identify 33 potential drug-target genes for RA-ILD, including three genes associated with the mechanism of action of cyclophosphamide. These findings offer a promising roadmap for developing targeted therapies, potentially shifting treatment strategies from broad immunosuppression to precise molecular interventions.