D-allose reprogrammes the mitophagy-mtDNA-cGAS-STING-ADM2 axis to restore nucleus pulposus cell homeostasis in intervertebral disc degeneration.

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.