Objectives Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Abnormal T-cell ubiquitination has been implicated in RA pathogenesis, yet its molecular mechanisms remain unclear. Methods Transcriptomic data from RA blood and synovial tissue were analyzed to identify differentially expressed genes (DEGs). Ubiquitination-related module genes were obtained using weighted gene co-expression network analysis (WGCNA), and their overlap with DEGs yielded blood-synovial ubiquitination-related genes (BS-UGs). Single-cell datasets were used to extract T-cell marker genes, and intersection analysis identified T-cell-specific ubiquitination genes (BS-TUGs). Machine learning algorithms (SVM-RFE and Boruta) screened key BS-TUGs. Immune infiltration, transcription factor (TF) regulation, and master regulators were explored. Finally, two-sample Mendelian randomization (MR) was performed to assess causal relationships between key genes and RA. Results A total of 521 BS-UGs and 21 candidate BS-TUGs were identified, from which six key genes (DOCK10, DGKA, NOP58, JAK3, GCC2, ANO9) were selected. These genes exhibited significant immune-cell correlations and were regulated by multiple TFs. MR analysis demonstrated a positive causal association between NOP58 (OR = 1.074, p = 0.001) and RA, and a negative association between GCC2 (OR = 0.928, p 0.001) and RA, without heterogeneity or pleiotropy. Conclusion Integrative dual-omics and MR analyses identified key ubiquitination-related T-cell genes driving RA pathogenesis. NOP58 and GCC2 represent potential causal biomarkers and therapeutic targets, offering novel insights into immune regulation and precision intervention in RA.
He et al. (Mon,) studied this question.