CD4 + T cell-derived exosomal miR-223-3p serves as a potential biomarker for systemic lupus erythematosus and attenuates lupus nephritis in NZBWF1/J mice.

Although emerging evidence links exosomal miRNAs to autoimmunity, the specific role of CD4 + T cell-derived exosomal miRNAs in systemic lupus erythematosus (SLE) remains incompletely understood. This study aimed to identify key exosomal miRNAs derived from CD4 + T cells in SLE and to assess their diagnostic and therapeutic potential. We found that CD4 + T cell-derived exosomal miR‑223‑3p was downregulated in SLE patients and demonstrated moderate diagnostic performance (AUC = 0.71, 95% CI: 0.65-0.77). When combined with conventional clinical markers, it provided incremental diagnostic value. Its correlation with clinical markers (C3/C4) was specific to the CD4 + T cell-derived exosomal fraction, distinguishing it from the plasma‑derived counterpart. Functionally, miR-223-3p overexpression inhibited the secretion of inflammatory cytokines and T cell apoptosis while promoting mitophagy via FBXW7. Additionally, it disrupted pathological T‑B cell interactions by suppressing BAFF and CD19 expression. In a murine lupus model (NZBWF1/J), administration of exosomal miR‑223‑3p alleviated lupus nephritis, as evidenced by reduced proteinuria, lower Anti‑dsDNA titers, and diminished renal immune complex deposition. Collectively, our study identified CD4 + T cell-derived exosomal miR‑223‑3p as a cell-origin-associated biomarker in SLE, while also acting as a pathogenic regulator through the FBXW7/mitophagy axis and modulation of T-B cell crosstalk. Its therapeutic efficacy in vivo supports its potential as a candidate for exosome‑based therapy in SLE, but the evidence remains preliminary.