Nanoparticle‐Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining Mitophagy‐Mediated CD8+T Cell Exhaustion

ABSTRACT 5‐Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. 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 high CD74 high CD8+T subgroup that were robustly expanded in SLE patients through single‐cell transcriptome sequencing (scRNA‐seq). CD7 high CD74 high 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‐seq). ScRNA‐seq and m5C‐seq were conjointly analyzed to screen m5C‐related 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)‐mediated mitophagy. Finally, we verified that nanoparticle‐delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane‐induced SLE mouse models. In conclusion, we identify an exhausted CD7 high CD74 high CD8+T cell subset and propose the crucial role of NSUN4/CD74‐induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.