CDIP1 as a novel therapeutic target in rheumatoid arthritis: WGCNA and machine learning-driven discovery of ubiquitination-mediated immune and apoptotic dysregulation

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and bone/cartilage destruction. Its pathogenesis is closely related to genetic, environmental factors and immune system abnormalities, such as dysregulation of pro-inflammatory cytokines, ROS accumulation and hypoxic microenvironment. Studies on the pathological mechanisms of Rheumatoid Arthritis (RA) focus on immune disorders, inflammatory microenvironment and genetic susceptibility. The relevant treatment schemes mainly target TNF-α, IL-6 and JAK-STAT pathways. Although existing therapies can partially alleviate symptoms, However, 30%-40% of patients still have drug resistance or relapse, and most patients have significant individual differences and lack predictive biomarkers. The diagnosis and treatment of rheumatoid arthritis (RA) continue to present significant challenges. Therefore, the analysis of RA heterogeneity mechanism and the development of novel targeted therapy strategies and dynamic monitoring markers are the keys for accurate diagnosis and treatment. In this study, we used WGCNA in combination with a variety of machine learning to screen CDIP1, a gene highly associated with rheumatoid arthritis, from the transcriptome data of synovial tissue of patients with rheumatoid arthritis, and analyzed its functional mechanism through single cells, interacting proteins and transcriptional regulation. CDIP1 is regulated by MYC, CREB1, SETDB1, and RAD21, and plays an important role in immune regulation and apoptosis regulation through ubiquitination modification, thus playing an important role in the occurrence and development of rheumatoid arthritis. This provides a new target for the diagnosis and treatment of rheumatoid arthritis. Background Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic synovial inflammation and progressive joint destruction. Although current therapies have improved disease management, the underlying molecular mechanisms driving RA pathogenesis remain incompletely understood, necessitating the identification of novel regulatory targets and biomarkers. Methods Through WGCNA and a variety of machine learning analysis, we identified CDIP1 as a potential immune-regulatory molecule implicated in RA. Differential expression analysis revealed a significant downregulation of CDIP1 in RA synovial tissues. To elucidate its functional role,we verified the role of CDIP1 in immune regulation through single-cell data, and we predicted CDIP1-interacting proteins using the BioGRID database and performed Gene Ontology(GO) and KEGG pathway enrichment analyses. Furthermore, upstream transcriptional regulators were explored via intersection analysis across five databases (hTFtarget, ChIP_Atlas, ENCODE, CHEA, GTRD), followed by co-expression analysis in GTEx blood samples. Results Our research identified CDIP1 as a key immune-regulatory molecule that is significantly downregulated in the synovial tissues of patients with rheumatoid arthritis (RA). CDIP1 had important role in immune response, apoptosis and DNA damage repair. CDIP1-interacting proteins were significantly enriched in biological processes and molecular functions related to protein ubiquitination, kinase activity, and molecular chaperoning. Notably, CDIP1 may participate in immune and apoptotic regulation via ubiquitin–proteasome pathway modulation. Transcription factors MYC, CREB1, SETDB1, and RAD21 showed strong positive correlations with CDIP1 expression (Pearson’s r > 0.64, p < 1e-69) and possessed high-confidence binding sites within the CDIP1 promoter region. Single-cell transcriptomic analysis further demonstrated consistent downregulation of these transcription factors in RA synovial fibroblasts, mirroring the expression pattern of CDIP1. Functional enrichment of these regulators revealed key roles in chromatin remodeling, gene expression, and myeloid leukocyte differentiation. Conclusion Our findings uncover a novel regulatory axis involving CDIP1 and its upstream transcriptional regulators, highlighting its dual role in protein homeostasis and inflammatory signaling modulation in RA. CDIP1 downregulation—potentially driven by impaired transcriptional control—may disrupt the balance of apoptosis, immune activation, and cell–cell communication, contributing to RA pathogenesis. This study reveals a new function of CDIP1, and provids a new molecular biomarker for the diagnosis and treatment of rheumatoid arthritis.