A novel angiogenesis-related gene signature predicting prognosis in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and is characterized by high recurrence and metastasis rates. A key feature of ccRCC is its rich vascular network, which supports tumor growth and metastasis through angiogenesis, the process of forming new blood vessels. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) pathway has shown efficacy in treating advanced ccRCC, but resistance often develops, highlighting the need for new therapeutic targets. We systematically screened differentially expressed genes (DEGs) between ccRCC and normal tissues using TCGA-KIRC data, and intersected them with angiogenesis-related genes from GeneCards and MSigDB. Survival analysis identified prognostic genes, and a multigene risk signature was established and validated using an independent GEO cohort (GSE29609). Functional analyses and immunohistochemistry were performed to explore the biological roles of the key gene RUNX1. A total of 27 ccRCC-related angiogenesis genes were identified, of which four formed a prognostic signature with strong predictive value. Among them, RUNX1 carried the greatest prognostic weight. Functional validation revealed that RUNX1 promotes ccRCC progression by regulating immune infiltration and lipid metabolism. In particular, RUNX1 expression was associated with enhanced CD8⁺ T-cell infiltration and upregulation of lipid metabolism genes such as FASN and SCD1. Our study identifies a novel angiogenesis-related prognostic signature for ccRCC and highlights RUNX1 as a key regulator linking tumor angiogenesis, immune infiltration, and lipid metabolism. Compared with conventional anti-VEGF therapies, targeting RUNX1 may provide broader therapeutic benefits and represents a promising translational strategy for improving ccRCC management.