Successful axonal regeneration is driven by evolutionarily conserved metabolic reprogramming. Successful axonal regeneration is driven by evolutionarily conserved metabolic reprogramming

Unlike mammals, zebrafish can regrow axons after injury and restore circuit function in the central nervous system (CNS). Mitochondria have been identified as key players in this process, but how different metabolic pathways work together to sustain regeneration remains unclear. Using RNA sequencing of adult zebrafish retinal ganglion cells (RGCs) after optic nerve crush injury, we demonstrate that oxidative phosphorylation is downregulated during axonal regrowth. Simultaneously, the thioredoxin antioxidant system is upregulated, likely to limit oxidative damage. Additionally, we observe an integrated upregulation of glycolysis and the pentose phosphate pathway during the initial regrowth phases, possibly to provide energy while supplying NADPH for biosynthesis and antioxidant responses. We show that this metabolic reprogramming is evolutionarily conserved, as it also occurs in the pro-regenerative mammalian Pten and Socs3 co-deletion model. Inhibiting glycolysis and thioredoxin in zebrafish impairs axonal regrowth, suggesting that targeting these pathways could enhance CNS regeneration in mammals. Overall design: Bulk RNA sequencing of FAC-sorted adult Tg(isl2b:eGFP)zc7Tg zebrafish retinal ganglion cells under the uninjured (naive) condition and at 1, 3, 6, 10, and 14 days post-optic nerve crush injury.