Targeting age-related cell-free DNA for prevention, early diagnosis and treatment of rheumatoid arthritis

Cell-free DNA (cf-DNA) refers to extracellular DNA fragments released during cell death, which have been observed to accumulate with advancing age. Elevated cf-DNA concentrations have been detected in the plasma and disease-affected tissues of patients with multiple disorders, particularly age-related autoimmune diseases such as rheumatoid arthritis (RA). Growing evidence supports the potential of cf-DNA as a biomarker for a broad spectrum of autoimmune and age-associated conditions, including cancer, systemic lupus erythematosus (SLE), and psoriasis. Fluctuations in cf-DNA levels and characteristics appear to be closely associated with disease onset, progression, severity, and prognosis. Importantly, emerging studies indicate that cf-DNA may not merely act as a passive biomarker but could also function as an active mediator contributing to RA pathogenesis through distinct immunological pathways. These insights suggest that cf-DNA represents a promising target for the development of innovative diagnostic, preventive, and therapeutic strategies. In this review, we summarize the current understanding of age-related cf-DNA in RA, highlight its potential immunopathological roles, and discuss recent advances in cf-DNA-based diagnostic tools, preventive approaches, and therapeutic interventions with possible clinical translational value.