The pentose phosphate pathway: a metabolic switch between sensory homeostasis and axonal repair
Aims: To determine whether the pentose phosphate pathway (PPP), a glucose-metabolising shunt that produces antioxidants and building blocks for cell repair, is essential for normal sensory function and nerve regeneration, with direct implications for the metabolic dysfunction driving diabetic peripheral neuropathy (DPN).
Methods: Proteomics and metabolomics of sciatic nerve axoplasm identified PPP enrichment in peripheral versus central axons. Rodent models of sciatic nerve crush and spinal cord injury, combined with neuronal transketolase overexpression and oral ribose supplementation, tested whether restoring PPP activity could rescue regeneration. Human sural nerve biopsies provided translational context.
Results: The PPP is selectively active in peripheral sensory axons. At baseline, it neutralises the oxidative stress generated by mechanical stimulation and disrupting it impairs normal touch and pressure sensing. After nerve injury, the PPP shifts gear: instead of making antioxidants, it produces the raw materials needed for new RNA and protein synthesis to drive regeneration. This switch does not happen in central (spinal cord) axons after injury, explaining in part why peripheral nerves can regenerate but central ones cannot. Reactivating the PPP, either by boosting the enzyme transketolase or by simply supplementing with oral ribose, restored axonal growth and improved functional recovery.
Conclusions: The PPP is a dual-purpose metabolic switch in peripheral sensory axons: a redox guardian at rest, and a regenerative engine after injury. Its failure in central axons is a key reason they cannot repair themselves.
Comments: This paper reframes peripheral axon metabolism in a way that is immediately relevant to DPN. In DPN, chronic hyperglycaemia diverts glucose into pathological collateral pathways (polyol, hexosamine, PKC, and AGE) at the direct expense of protective shunts. The demonstration that PPP suppression intrinsically disrupts mechanosensory ROS homeostasis provides a compelling axon-autonomous mechanism for the early sensory loss and mechanical allodynia characteristic of DPN, independent of vascular or glial contributions. The peripheral-versus-central contrast is particularly thought-provoking. If chronic hyperglycaemia pushes peripheral sensory axons into a PPP-inactive state, it may be rendering them metabolically similar to central axons and robbing them of their intrinsic regenerative advantage. This is a new and testable conceptual frame for why DPN nerve fibre loss is so poorly reversible. The TKT–thiamine axis is not new to the DPN field: benfotiamine trials have been conducted, with underwhelming clinical results. This paper, however, recontextualises TKT not merely as a detoxifier of glycolytic overflow, but as an active regulator of axonal bioenergetic identity, a conceptually important distinction that argues for more nuanced pathway-level intervention and axon-targeted delivery rather than simple enzyme supplementation. The human sural nerve data deserve scrutiny: biopsy-based metabolomics is inherently cross-sectional, and whether PPP suppression precedes or follows intraepidermal nerve fibre loss in established DPN cannot be resolved here. The regenerative SCI data, while compelling mechanistically, should be extrapolated to DPN-associated nerve degeneration with caution, the injury context, fibre-type specificity, and metabolic milieu differ substantially. The most actionable near-term opportunities lie in two areas: first, examining whether PPP metabolite profiles in skin punch biopsies stratify DPN patients by regenerative potential; and second, revisiting axon-targeted ribose or TKT activator delivery, bypassing the systemic thiamine pharmacology that confounded earlier trials.
Ali Jaafar
Reference. Song Y, Luengo-Gutierrez L, Sagi-Kiss V, Kong G, Huang H, Steinruecke M, Zhou L, Yuan Z, De Virgiliis F, Pap I, Decourt C, Yan Y, Park HH, Zhang H, Wei J, Want E, Tong X, Takats Z, Di Giovanni S. A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration. Cell. 2026 Feb 19;189(4):1211-1227.e25. doi: 10.1016/j.cell.2025.12.003. Epub 2026 Jan 5. PMID: 41494529.
