Metabolic alterations after traumatic neural injury: Mechanistic insights and potential translational targets for axon regeneration

Metabolism not only provides essential substances and energy for cells through catabolism and anabolism but also exerts broader regulatory roles through metabolic enzymes and products that influence gene expression, thereby maintaining homeostasis. Upon neuronal injury, metabolic changes in both neurons and supporting cells influence neuronal survival and regeneration by regulating energy supply, substrate availability, regeneration-related gene expression, and cell-cell metabolic interactions. Axon regeneration is a key process in neural repair after injury. Beyond the nervous system itself, systemic factors such as diet, exercise, circadian rhythms, and psychological stress also play crucial roles in axon regeneration through interorgan metabolic communication and microbiota-host metabolic cross-talk. In this Review, we summarize advances in understanding metabolic alterations during axon regeneration, with a focus on glycometabolism, lipid metabolism, protein degradation, mitochondrial activity, and systemic factor-driven metabolic cross-talk between nervous and non-nervous systems. We also highlight the therapeutic potential of metabolites themselves, analyze distinct metabolic responses after injury in the peripheral and central nervous systems, and discuss their spatiotemporal dynamics and cell type specificity. Last, we propose that successful neural repair requires the establishment of a systemic pro-regenerative state throughout the entire body.