A Glycolytic Shunt via the Pentose Phosphate Pathway is a Metabolic Checkpoint for Nervous System Sensory Homeostasis and Axonal Regeneration

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 injury-induced axonal regeneration. We show that the PPP is enriched and active in sciatic nerve axoplasms, where it maintains redox balance via NADPH production, enabling normal mechanical sensation. Following sciatic nerve injury, the PPP is required for regeneration by fueling ribonucleotide synthesis through ribose-5-phosphate production. 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 reveal a dual role for the PPP as metabolic rheostat in sensory neuron physiology and regeneration and highlight its therapeutic potential for central nervous system repair. Overall design: RNA sequencing profiles of 8 weeks C57BL/6J mice with either AAV-GFP or AAV-Tkt virus injected through scaitic nerves for 4 weeks, L4-6 dorsal root ganglia neurons were extracted 72hr following SCI. RNA sequencing profiles of 8 weeks C57BL/6J mice L4-6 dorsal root ganglia neurons were extracted 72hr following SCI with either 10% ribose or vehicel treatment.