Hyal2, short for hyaluronidase 2, is one of the hyaluronidases in vertebrates. It hydrolyzes high molecular mass hyaluronan to approximately 20 kDa intermediates, and has an acidic pH-optimum with relatively low activity compared to other hyaluronidases. Initially considered a lysosomal enzyme, it can also be on the cell surface via a GPI anchor. Hyal2 is involved in many physiological and pathological processes, such as tumor-related events, inflammation, and embryogenesis [1].

In bladder cancer, Hyal2-expressing tumor-associated myeloid cells contribute to hyaluronan degradation, leading to the accumulation of inflammatory and proangiogenic low molecular weight hyaluronan fragments, thus mediating cancer-related inflammation [2]. HYAL2 deficiency in humans, as seen from clinical and genomic investigations, is associated with orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, similar to phenotypes in Hyal2 knockout mice [3]. Also, blood-based HYAL2 methylation shows an association with pre-clinical coronary heart disease and stroke, suggesting its potential as a biomarker [4]. In endothelial cells, Hyal2 regulates low shear stress-induced injury of the glycocalyx via the LKB1/AMPK/NADPH oxidase signaling cascades [5]. And in thyroid tumors, the DNA methylation level of HYAL2 gene is significantly correlated with early-stage papillary thyroid cancer, potentially serving as a biomarker for differentiating malignant from benign tumors [6].

In conclusion, Hyal2 plays essential roles in multiple biological processes and disease conditions. Studies using gene knockout mouse models, like those in Hyal2-deficient humans, have revealed its significance in craniofacial development, cancer-related inflammation, cardiovascular diseases, and endothelial cell function. These findings help us understand the underlying mechanisms of these diseases and may provide new directions for diagnosis and treatment.