Abstract
BACKGROUND: Hypoxia and glycolysis play crucial roles in tumor progression, yet their association with kidney renal clear cell carcinoma (KIRC) remains unclear. Here, a novel prognostic model was developed with hypoxia-glycolysis-related genes (HGRGs) in KIRC, providing insights to elucidate the aforementioned uncertainties. METHODS: Transcriptomic information and clinical characteristics of KIRC were acquired from The Cancer Genome Atlas Program, ArrayExpress database, and Gene Expression Omnibus. Significant HGRGs were identified, and a prognostic model was constructed. We performed enrichment analysis, tumor mutational burden (TMB), tumor microenvironment), and drug sensitivity analyses to elucidate potential mechanisms of HGRGs. RESULTS: The prognostic model based on five HGRGs (ADORA2B, TGFA, FBP1, HK3, PDHB) effectively predicted the clinical outcome. The nomogram, which integrates a prognostic model and clinical information, demonstrated superior performance. Low-risk patients were enriched in fatty acid metabolism and peroxisome pathways, exhibited higher immunotherapy responsiveness, and showed greater sensitivity to Gefitinib and Afatinib. High-risk patients exhibited activation of inflammatory and profibrotic pathways, an elevated TMB, immunosuppressive microenvironments, and greater sensitivity to Topotecan and Irinotecan. RT-qPCR validated the expression of HGRGs across selected cell lines. CONCLUSIONS: The prognostic model derived from five HGRGs demonstrates excellent clinical value in predicting prognosis and guiding therapeutic strategies in KIRC.