Abstract
Abstract
Intervertebral disc degeneration (IVDD) is driven by progressive loss of nucleus pulposus cell (NPC) homeostasis, yet the stress-responsive mechanisms governing this process remain incompletely defined. Here, we identify a mitochondrial stress–innate immune signalling axis in which impaired mitophagy promotes mitochondrial DNA (mtDNA) leakage, aberrant activation of the cGAS–STING pathway, suppression of the cytoprotective peptide adrenomedullin 2 (ADM2) and consequent NPC senescence and apoptosis. Using integrated transcriptomic analyses, genetic models and human disc specimens, we establish ADM2 as a previously unrecognized downstream effector linking innate immune activation to disc cell fate control. Importantly, we demonstrate that D-allose, a naturally occurring rare sugar with an excellent safety profile, reprogrammes this pathogenic axis by restoring mitophagy, limiting cytosolic mtDNA accumulation, suppressing cGAS–STING signalling and preserving ADM2-dependent cytoprotection. In vivo, D-allose markedly attenuates IVDD, with genetic ablation of STING providing complementary evidence that suppression of this pathway confers robust protection against degeneration. Together, these findings define a mitophagy–mtDNA–cGAS–STING–ADM2 axis as a central regulator of IVDD and reveal D-allose as a physiologically compatible strategy for rebalancing mitochondrial stress signalling and restoring NPC homeostasis.