Pan-Cancer Bioinformatics and Drug-Repurposing Analysis of HYAL1 and HYAL2 as Potential Prognostic and Immunomodulatory Biomarkers

HYAL1 and HYAL2 are the predominant mammalian hyaluronidases in somatic cells that are implicated in extracellular matrix remodeling and cancer biology. Their roles have not yet been systematically tackled in any comprehensive pan-cancer study. In this study, we investigated HYAL1 and HYAL2 in 33 types of cancer using public databases through TIMER 2.0, GEPIA 2, UALCAN, cBioPortal, and Kaplan–Meier Plotter. The expression profiles of the two genes were unique, and their mutation incidence was low. Significant differences in promoter methylation levels between cancerous and normal tissues were observed. Their expression was clinically relevant and related to overall survival in a cancer-type–specific manner: high expression was a risk factor for some cancers and a protective factor in other cancers like kidney cancer. Moreover, HYAL1 and HYAL2 showed tumor-specific correlations with infiltration of CD8⁺ T cells, indicating impacts on the immune microenvironment. We conducted structure-based molecular docking using HYAL1 (PDB: 2PE4) and an AlphaFold model of HYAL2. Several FDA-approved drugs presented favorable binding affinities: HYAL1-selective (-10.775 kcal/mol, CHEMBL1200507), HYAL2-selective (-9.352 kcal/mol, CHEMBL1200455), and potential dual binders (-8.8/-8.1 kcal/mol) (CHEMBL58). Our preliminary data suggest HYAL1 and HYAL2 may function as context-dependent biomarkers associated with cancer prognosis and immune microenvironment characteristics. These docking results indicate that the identified compounds are potential candidates for further investigation. However, our comprehensive computational analyses provide insights into the potential roles of HYAL1 and HYAL2 across multiple cancers, but experimental and clinical studies are required to validate their biological functions and therapeutic relevance.