Heparan sulfate sulfation modification in airway mucosal barrier: biosynthetic regulation, pathological implications, and therapeutic targets in allergic respiratory diseases.

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan essential for airway mucosal barrier function. Its biological activities are determined by the "sulfation code" generated through N-deacetylase/N-sulfotransferases (NDST1-4) and O-sulfotransferases. Emerging evidence indicates that HS sulfation operates within a narrow homeostatic range - a "rheostat" - where both insufficient and excessive sulfation disrupt barrier integrity and promote inflammation. This review proposes the HS sulfation rheostat model as a unifying framework for allergic respiratory diseases. We examine the HS biosynthetic machinery and its regulation at transcriptional, epigenetic, and metabolic levels, with emphasis on histone lactylation as a metabolic-epigenetic rheostat for HS enzyme expression. We summarize HS functions within the homeostatic range, including glycocalyx integrity, tight junction regulation, and growth factor signaling. We then discuss rheostat dysregulation in allergic airway inflammation, focusing on evidence from NDST1-deficient mice demonstrating that HS N-sulfation mediates eosinophil recruitment, chemokine sequestration, and airway remodelling. Key controversies are appraised, including the NDST1 versus NDST3 debate, cell-type-specific functions, and the translational gap. Finally, we highlight therapeutic strategies for restoring the rheostat, including non-anticoagulant heparin derivatives, defined HS oligosaccharides, heparanase inhibitors, and HS glycomimetics. Understanding the HS sulfation rheostat and its regulation through the glycoepigenetics axis may identify new therapeutic targets for allergic rhinitis, asthma, and related airway diseases. Compartment-specific set points are emphasized throughout: epithelial sulfation reinforces barrier integrity, whereas endothelial and leukocyte sulfation governs leukocyte recruitment and chemokine presentation.