Mitochondrial DNA in systemic lupus erythematosus: pathogenic mechanisms, clinical biomarkers, and precision therapeutic strategies.

Mitochondrial DNA (mtDNA) is increasingly recognized as an active driver of immune dysregulation in systemic lupus erythematosus (SLE), yet most existing reviews treat it as a single damage signal rather than a multifunctional pathological mediator. This review presents an integrated framework examining mtDNA as a central hub linking mitochondrial dysfunction to systemic autoimmunity. We conducted a comprehensive synthesis of published evidence on mtDNA biology, its dysregulation in SLE, organ-specific injury mechanisms, and the clinical landscape of mtDNA-targeted therapeutic strategies. In SLE, intracellular mtDNA depletion coexists paradoxically with markedly elevated circulating cell-free mtDNA, a pattern correlating with disease activity and organ involvement. Sequential cytoplasmic and extracellular release of mtDNA engages cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Toll-like receptor 9 (TLR9), and inflammasome platforms, establishing self-amplifying interferon and pro-inflammatory circuits that drive multi-organ pathology. We consolidate emerging evidence for mtDNA-related parameters as clinical biomarkers and propose a provisional patient stratification framework distinguishing two pathological subtypes with distinct therapeutic implications. Among current therapeutic strategies, N-acetylcysteine (NAC) and metformin carry the strongest clinical evidence, while cGAS-STING inhibitors and TLR9 antagonists represent compelling emerging candidates. mtDNA operates as an integrative pathological hub in SLE, and its dysregulation pattern carries both diagnostic and therapeutic significance. Incorporating mtDNA-based biomarkers into clinical monitoring and developing precision strategies targeting mtDNA-driven inflammatory circuits represent important steps toward individualized SLE management.