Lymphangiogenesis-related prognostic gene signature for hepatocellular carcinoma identified by integrative multi-omics and causal inference

BACKGROUNDHepatocellular carcinoma (HCC) is a leading cause of cancer-related death, yet the prognostic significance of lymphangiogenesis (LYM)-related genes remains poorly defined.Systematic evaluation of their clinical value and biological impact is lacking.AIM To identify and validate LYM-related prognostic genes in HCC. METHODSWe integrated differential expression, Mendelian randomization, and univariate Cox regression to screen genes, then built a prognostic model.Validation included GSEA, immune microenvironment profiling, drug sensitivity analysis, reverse transcriptionquantitative polymerase chain reaction, and single-cell RNA sequencing. RESULTSWe identified 6283 differentially expressed genes and 3 prognostic genes, risk factors LOXL2/PLXDC1 and protective COL15A1, forming a robust model.GSEA linked risk groups to peroxisome pathways.All three genes correlated positively with astrocytes.Drug analysis revealed 101 compounds with differential sensitivity.Single-cell RNA sequencing highlighted T cells and macrophages.Clinical reverse transcriptionquantitative polymerase chain reaction confirmed COL15A1 and LOXL2 expression trends.CONCLUSION COL15A1, LOXL2, and PLXDC1 are key LYM-related prognostic biomarkers for HCC risk stratification.