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Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7\n                    <jats:sup>high<\/jats:sup>\n                    CD74\n                    <jats:sup>high<\/jats:sup>\n                    CD8+T subgroup that were robustly expanded in SLE patients through single\u2010cell transcriptome sequencing (scRNA\u2010seq). CD7\n                    <jats:sup>high<\/jats:sup>\n                    CD74\n                    <jats:sup>high<\/jats:sup>\n                    CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C\u2010seq). ScRNA\u2010seq and m5C\u2010seq were conjointly analyzed to screen m5C\u2010related therapeutic targets for SLE, and NOP2\/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44\/mTOR (mechanistic target of rapamycin kinase)\u2010mediated mitophagy. Finally, we verified that nanoparticle\u2010delivered siRNA against\n                    <jats:italic>Nusn4<\/jats:italic>\n                    decreased autoimmune reaction kidney damage in both spontaneous and pristane\u2010induced SLE mouse models. In conclusion, we identify an exhausted CD7\n                    <jats:sup>high<\/jats:sup>\n                    CD74\n                    <jats:sup>high<\/jats:sup>\n                    CD8+T cell subset and propose the crucial role of NSUN4\/CD74\u2010induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70311","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T04:14:50Z","timestamp":1754280890000},"source":"Crossref","is-referenced-by-count":15,"title":["Nanoparticle\u2010Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining Mitophagy\u2010Mediated CD8+T Cell Exhaustion"],"prefix":"10.1002","volume":"6","author":[{"given":"Bincheng","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology The Second Affiliated Hospital of Xi'an Jiaotong University  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