The emerging clinical relevance of cell-free DNA in lupus: from mechanistic insights to therapeutic opportunities.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease often characterised by dysregulated immune responses to self-DNA. Emerging evidence highlights the role of cell-free DNA (cfDNA) in promoting immune activation in SLE. Cell-free DNA is released primarily during cell death and is cleared by nucleases such as DNASE1L3. This review explores how molecular characteristics of cfDNA, such as fragment length, end motifs, jaggedness, and epigenetic modifications, serve as biomarkers of disease activity and may contribute to pathogenesis. The review then explains how deficiencies in DNASE1L3 alter cfDNA fragmentation, increase immunogenic potential, and enhance type I interferon signalling via plasmacytoid dendritic cells, driving B-cell differentiation and anti-double-stranded DNA (anti-dsDNA) antibody production. We also discuss how autoantibodies can cross-react to neutralise DNASE1L3, impeding DNA clearance and exacerbating inflammation. We conclude by highlighting how these findings underpin the dual role of cfDNA as both a disease mediator and a diagnostic tool and support the ongoing development of IFN-I and pDC-targeting therapies, which show promising clinical relevance. Moreover, we discuss how large-scale validation and standardisation are essential for translating these molecular insights into precision medicine for diverse SLE populations.