Angiogenic Prognostic Signature for Stratification in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Angiogenesis drives HCC progression, but reliable biomarkers remain limited. Methods: We analyzed angiogenesis‑related genes (ARGs) using TCGA data, constructed a prognostic signature via LASSO‑Cox regression, and validated it in ICGC and real‑world HCC cohorts. Functional experiments (in vitro and in vivo) were performed for Secretory phosphoprotein 1 (SPP1). Single‑cell RNA‑seq data mapped cellular sources of signature genes. Drug sensitivity (GDSC2) and sorafenib‑treated GEO data assessed therapy response. Results: A four-gene ARG signature (APOH, SLCO2A1, SPP1, VTN) stratified HCC patients into high- and low-risk groups with distinct survival, validated in external cohorts. The high‑risk group showed enriched immune checkpoint expression and stromal activity. Single‑cell analysis revealed SPP1 mainly from macrophages and hepatocytes; VTN, APOH, and SLCO2A1 from monocyte/macrophage subsets. SPP1 knockdown suppressed endothelial angiogenesis in vitro and in vivo. High‑risk patients exhibited reduced sorafenib sensitivity (higher IC50), and sorafenib treatment downregulated APOH, SPP1, and VTN but not SLCO2A1. Conclusion: We established a robust ARG‑based prognostic signature for HCC that improves risk stratification and highlights links between angiogenesis, immune microenvironment, and drug response.