Misplaced DNA sensing in intervertebral disc degeneration: mitochondrial stress, sterile inflammation, pyroptosis, and DNA clearance.

Intervertebral disc degeneration (IVDD) links cellular stress to persistent sterile inflammation, but the initiating role of misplaced DNA remains uncertain. This review examines mitochondrial DNA (mtDNA) and other self-DNA through a source-compartment-sensor-output framework. Cytosolic DNA can engage cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, whereas endolysosomal DNA can engage Toll-like receptor 9 (TLR9). Disc-cell experiments and induced animal models support contributions to inflammatory signaling and pyroptotic injury. Genetic findings vary across aging models, limiting universal claims about STING-driven degeneration. We distinguish resident-cell responses from immune-cell recruitment, pathological stress from physiological adaptation, and experimental pathway dependence from disease initiation. We also assess extracellular nucleic-acid capture as preliminary intervention evidence without assuming that native matrix retention or endogenous nuclease failure has been established. The framework identifies where direct disc evidence supports a mechanism and where trafficking, causality or clearance remains unresolved. Priorities include source-selective perturbation, temporal and compartment-resolved measurements, and independent structural and pain-related outcomes. Clinical translation requires validation beyond preclinical structural improvement.