The role of DNASE1L3 in systemic lupus erythematosus: from pathogenesis to clinical implications

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by multi-organ damage, a complex interplay of immune dysregulation, and antibodies against nuclear macromolecules like DNA. Among these, anti-dsDNA antibodies are not only crucial diagnostic markers but also active participants in disease pathogenesis, forming immune complexes that deposit in various tissues and trigger inflammation. Emerging research has highlighted the critical role of Deoxyribonuclease 1-Like 3 (DNASE1L3), a secreted endonuclease, in maintaining homeostasis of cell-free DNA (cfDNA). Deficiencies or dysfunction of DNASE1L3, whether due to genetic mutations or neutralizing autoantibodies, lead to impaired clearance of cfDNA derived from apoptotic cells, microparticles, and Neutrophil Extracellular Traps (NETs). This accumulation of cfDNA plays an important role in SLE. This review explores the characteristics of DNASE1L3, the current status of research on the mechanisms through which its defects contribute to SLE pathogenesis, and its promising potential in the clinical diagnosis, monitoring, and treatment of this complex disease.