Hyaluronidase: structure, mechanism of action, diseases and therapeutic targets

Abstract Hyaluronidase (HAase), a family of enzymes critical for regulating physiological and pathological states, catalyzes the degradation of hyaluronic acid (HA), a key component of the extracellular matrix (ECM). By modulating ECM composition and cellular signaling pathways, HAase plays a pivotal role in diverse biological processes, including wound healing, tissue regeneration, and tumor progression. This review systematically elucidates the classification, biological sources, structural diversity, and catalytic mechanisms of HAase, emphasizing its dynamic involvement in disease pathogenesis and diagnostic potential. Furthermore, the article explores innovative therapeutic strategies centered on HAase modulation. HAase inhibitors emerge as promising tools for maintaining HA homeostasis, with implications in anti-inflammatory, antimicrobial, and antitumor therapies by blocking excessive HA degradation. Concurrently, HAase-mediated drug delivery systems represent a paradigm shift in overcoming biological barriers, enhancing bioavailability, and optimizing therapeutic outcomes through ECM remodeling. Notably, the synergy between HAase and immunotherapeutic modalities, such as checkpoint inhibitors and adoptive cell therapies, demonstrates synergistic antitumor effects by reshaping the tumor microenvironment (TME) and augmenting immune cell infiltration. Nevertheless, numerous challenges persist in the clinical application of hyaluronidase, including its immunogenicity, safety, application limitations and ethical considerations. This review synthesizes current research advances and unresolved issues, integrating molecular insights with translational perspectives, aiming to provide a more comprehensive and in-depth understanding of hyaluronidase and to advance clinical therapeutic strategies for hyaluronidase.