Multiomics Characterization of HAO2 Expression and Its Clinical Associations in Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) exhibits extensive metabolic reprogramming and tumor microenvironmental heterogeneity, contributing to variable outcomes and treatment responses. Hydroxyacid oxidase 2 (HAO2) has been implicated in metabolic regulation, but its clinical and biological relevance in RCC remains incompletely characterized. We integrated transcriptomic, proteomic, genomic, and single-cell RNA-sequencing data to characterize HAO2 expression, clinicopathological associations, metabolic and immune features, and treatment-related outcomes. Exploratory drug-sensitivity associations were evaluated using the Genomics of Drug Sensitivity in Cancer database and pRRophetic. HAO2 expression was consistently reduced across multiple RCC datasets and showed tumor-normal discrimination with area under the curves ranging from 0.73 to 0.97. Low HAO2 expression was associated with advanced stage and shorter overall survival. HAO2 expression was positively associated with metabolic programs and distinct immune microenvironmental features. In the CheckMate-025 cohort, higher HAO2 expression was associated with longer overall survival in both treatment arms. Single-cell analysis showed reduced HAO2 expression in malignant renal epithelial cells. Exploratory pharmacogenomic analysis identified associations between HAO2 expression and drug sensitivity. HAO2 downregulation is associated with advanced disease, unfavorable survival, and distinct metabolic and immune features in RCC. HAO2 represents a candidate tissue-associated biomarker warranting further experimental and prospective validation.