Hyal2, or 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. It was initially considered a lysosomal enzyme but can also be on the cell surface via a GPI anchor. It is present in many tissues except the adult brain where its gene is silenced by methylation after birth. It is involved in processes like tumor growth, inflammation, and frog embryogenesis [1].

In bladder cancer, Hyal2-expressing tumor-associated myeloid cells can enhance extracellular hyaluronan (HA) breakdown, leading to the accumulation of small HA fragments, which are related to increased production of inflammatory cytokines, chemokines, and angiogenic factors. IL1β can stimulate Hyal2 activity, and CD44-mediated signaling is important in regulating its HA-degrading function [2]. Biallelic HYAL2 variants in humans cause a disorder with orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, similar to phenotypes in Hyal2 knockout mice. Missense variants can cause protein instability and absence of HYAL2 on the cell surface [3]. Blood-based HYAL2 methylation is associated with the risk of coronary heart disease and stroke, and the combination of four HYAL2 methylation sites can effectively distinguish cases without hypertension from controls [4].

In conclusion, Hyal2 plays a significant role in multiple biological processes and disease conditions. Its functions in tumor-related inflammation, a disorder with specific congenital phenotypes, and as a potential biomarker for cardiovascular diseases are revealed through model-based research, especially the phenotypes of Hyal2 knockout mice, which contribute to understanding these disease areas.