Glycosaminoglycans in axon growth and regeneration: molecular mechanisms and therapeutic implications.

Glycosaminoglycans (GAGs) are a structurally and chemically diverse family of sulfated polysaccharides that constitute a major component of the neural extracellular matrix and cell surface proteoglycans, where they exert pivotal regulatory functions in axon growth, guidance, synaptic organization, and regeneration. By forming highly specific and context-dependent interactions with axonal receptors, GAGs orchestrate the spatial patterning and temporal dynamics of signaling events after injury. Accumulating evidence indicates that the biological activities of GAGs are not dictated merely by their presence but are finely tuned by their sulfation codes, chain length, and domain organization. Recent mechanistic studies have revealed that distinct GAG species, particularly chondroitin sulfate (CS) and heparan sulfate (HS), exert opposing effects on axonal behavior through shared receptor systems. In the injured central nervous system (CNS), CS-rich extracellular matrices, prominently associated with reactive astrocytes and perineuronal nets, act as potent inhibitors of axon regeneration. These inhibitory effects are mediated through selective engagement of receptors such as protein tyrosine phosphatase sigma (PTPσ) leading to suppression of cytoskeletal dynamics and growth cone motility. In contrast, specific HS motifs promote axon elongation by inhibiting PTPσ. Based on these insights, therapeutic strategies targeting GAG biology have gained considerable attention. Approaches such as enzymatic digestion of inhibitory CS chains, development of synthetic or biomimetic GAGs, modulation of sulfation patterns, and gene editing of GAG-modifying enzymes have demonstrated encouraging efficacy in preclinical models of spinal cord injury, traumatic brain injury, and neurodegenerative disorders. Together, these findings indicate GAGs not only as passive structural components but as active, druggable regulators of axon growth and regeneration. This review integrates current advances in GAG structural biology, receptor interactions, and enzymatic regulation to provide a comprehensive framework for understanding how GAGs govern axonal behavior. We highlight unresolved questions and emerging opportunities for exploiting GAG-mediated mechanisms as actionable targets for next-generation neurorestorative therapies.