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Glycosaminoglycans (GAGs) are highly negatively charged polysaccharides that play essential roles in numerous physiological and pathological processes through their interactions with proteins. These interactions govern cellular signaling, inflammation, coagulation, and recognition. Surface Plasmon Resonance (SPR) has emerged as a key biophysical technique for label-free, real-time characterization of biomolecular interactions, offering insights into binding kinetics, affinity, and specificity. SPR-based approaches to glycosaminoglycan–protein interaction studies offer powerful tools for elucidating the roles of GAGs in a wide range of physiological and pathological processes. In this review, we systematically discuss experimental strategies, data analysis methods, and representative applications of SPR-based glycosaminoglycan–protein interactions. Special attention is given to the challenges associated with GAG heterogeneity and immobilization, as well as recent technological advances that enhance sensitivity and throughput. To our knowledge, this review represents one of the first systematic and up-to-date summaries specifically focused on recent advances in applying SPR to the study of glycosaminoglycan–protein interactions. 

Surface plasmon resonance (SPR) is a powerful tool for analyzing biomolecular interactions and is widely used in basic biomedical research and drug discovery. Heparan sulfate (HS) is a linear complex polysaccharide and a key component of the extracellular matrix and cell surfaces. HS plays a pivotal role in maintaining cellular functions and tissue homeostasis by interacting with numerous proteins, making it essential for normal physiological processes and disease states. Deciphering the interactome of HS unlocks the mechanisms underlying its biological functions and the potential for novel HS-related therapeutics. This review presents an overview of the recent advances in the application of SPR technology to HS interactome research. We discuss methodological developments, emerging trends, and key findings that illustrate how SPR is expanding our knowledge of HS-mediated molecular interactions. Additionally, we highlight the potential of SPR-based approaches in identifying novel therapeutic targets and developing HS-mimetic drugs, thereby opening new avenues for intervention in HS-related diseases.