{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T07:03:58Z","timestamp":1772435038594,"version":"3.50.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>NOP58<\/jats:italic>\n                      (OR = 1.074, p = 0.001) and RA, and a negative association between\n                      <jats:italic>GCC2<\/jats:italic>\n                      (OR = 0.928, p &amp;lt; 0.001) and RA, without heterogeneity or pleiotropy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Integrative dual-omics and MR analyses identified key ubiquitination-related T-cell genes driving RA pathogenesis.\n                      <jats:italic>NOP58<\/jats:italic>\n                      and\n                      <jats:italic>GCC2<\/jats:italic>\n                      represent potential causal biomarkers and therapeutic targets, offering novel insights into immune regulation and precision intervention in RA.\n        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China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The Third Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]},{"name":"Department of Foot Surgery, The Third Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghong","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The Third Hospital of Hebei Medical University","place":["Shijiazhuang, Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid 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