A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Homeostasis and repair in the nervous system are thought to rely on distinct molecular programs. Here, we uncover an unexpected role for the pentose phosphate pathway (PPP) in peripheral sensory axons, where it supports both homeostatic mechanosensation and axonal regeneration after injury. We show that the PPP is enriched and active in sciatic nerve axoplasms, where it maintains redox balance via NADPH production, enabling physiological mechanical sensation. However, following sciatic nerve injury, the PPP is required for regeneration by fueling ribonucleotide synthesis through ribose-5-phosphate. In contrast, this pathway remains inactive after spinal cord injury (SCI), contributing to regenerative failure. Reactivation of the PPP, through neuronal transketolase overexpression or oral ribose supplementation, promotes metabolic reprogramming, restores sensory and motor axonal growth, and improves neurological recovery after SCI. These findings propose the PPP as a metabolic checkpoint in sensory neuron physiology and regeneration, highlighting its therapeutic potential for central nervous system repair.
Date Issued
2026-02-19
Date Acceptance
2025-12-03
Citation
Cell, 2026, 189 (4), pp.1211-1227.e25
ISSN
0092-8674
Publisher
Elsevier BV
Start Page
1211
End Page
1227.e25
Journal / Book Title
Cell
Volume
189
Issue
4
Copyright Statement
©2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41494529
PII: S0092-8674(25)01379-0
Subjects
TKT
axon regeneration
homeostasis
mechanical sensation
nerve injury
neuronal metabolism
pentose phosphate pathway
ribose
spinal cord injury
transcription
Pentose Phosphate Pathway
Animals
Axons
Nerve Regeneration
Mice
Homeostasis
Sciatic Nerve
Spinal Cord Injuries
Glycolysis
Sensory Receptor Cells
Mice, Inbred C57BL
Female
Transketolase
NADP
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2026-01-05