The silent regulators: non-coding RNAs and Epstein–Barr virus at the crossroads of lupus pathogenesis

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease driven by immune dysregulation, chronic inflammation, and loss of immune tolerance. Increasing evidence suggests that non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are involved in the fine regulation of immune responses, epigenetic changes, and cytokine signaling in SLE. Their altered expression has been associated with disease activity, specific clinical phenotypes, and treatment response, supporting their potential as biomarkers. Epstein-Barr virus (EBV), a long-suspected contributor to SLE, may further shape disease through persistent immune activation, molecular mimicry, and modulation of host ncRNA pathways. In this review, we examine how EBV and ncRNA dysregulation may converge in autoreactive B cells and other immune compartments to promote the loss of tolerance and the development of clinically distinct forms of SLE. We also discuss the implications of this axis for biomarker development and emerging therapeutic strategies, including personalized immune-targeted approaches.Non-coding RNAs have potential as biomarkers of disease activity and clinical heterogeneity. EBV and ncRNAs may converge to amplify immune dysregulation in SLE. EBV-encoded proteins may reshape host regulatory programs linked to autoreactive B-cell activation. The EBV-ncRNA axis may help refine patient stratification for targeted therapies. Immune-targeted therapies, such as CAR-T, may benefit from EBV- and ncRNA-based biomarkers.