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Peer-reviewedCC BY 4.0Experimental & Molecular Medicine

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

  • Zhuoyang Zhao1,2,3
  • Jiamin Li1,2,3,4
  • Linchuan Lei1,2,3
  • Yanting Chen1,2,3,4
  • Zhe Li1,2
  • Yuhua Zhang5
  • Zhaomin Zheng1,2,6
  • Hua Wang1,2,6
  • Fan Chen7
  • Jianru Wang1,2,6
7 affiliations
  1. 1Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
  2. 2Guangdong Province Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080 PR China
  3. 3Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
  4. 4Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055 People’s Republic of China
  5. 5Kinesphere Lab, Irvine High School, 4321 Walnut Ave, Irvine, California 92604 USA
  6. 6Pain Research Center, Sun Yat-Sen University, Guangzhou, 510080 China
  7. 7Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026dallose,
  title = {{D-allose reprogrammes the mitophagy–mtDNA–cGAS–STING–ADM2 axis to restore nucleus pulposus cell homeostasis in intervertebral disc degeneration}},
  author = {Zhuoyang Zhao and Jiamin Li and Linchuan Lei and Yanting Chen and Zhe Li and Yuhua Zhang and Zhaomin Zheng and Hua Wang and Fan Chen and Jianru Wang},
  journal = {Experimental \& Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s12276-026-01844-7},
  url = {https://doi.org/10.1038/s12276-026-01844-7},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - D-allose reprogrammes the mitophagy–mtDNA–cGAS–STING–ADM2 axis to restore nucleus pulposus cell homeostasis in intervertebral disc degeneration
AU  - Zhuoyang Zhao
AU  - Jiamin Li
AU  - Linchuan Lei
AU  - Yanting Chen
AU  - Zhe Li
AU  - Yuhua Zhang
AU  - Zhaomin Zheng
AU  - Hua Wang
AU  - Fan Chen
AU  - Jianru Wang
PY  - 2026
DA  - 2026/10/01
JO  - Experimental & Molecular Medicine
DO  - 10.1038/s12276-026-01844-7
UR  - https://doi.org/10.1038/s12276-026-01844-7
AB  - 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.
SN  - 1226-3613
SN  - 2092-6413
ER  -