The inflammatory UPR-IFNG axis reveals LBP as a survival and immunotherapy-response marker in hepatocellular carcinoma

Background Liver hepatocellular carcinoma (LIHC) remains difficult to stratify because tumor heterogeneity and an immunosuppressive microenvironment limit immune checkpoint blockade (ICB). The unfolded protein response (UPR) and interferon-gamma (IFNG) signaling connect cellular stress with tumor inflammation, but clinically interpretable biomarkers linking these programs to prognosis and treatment response remain limited. Methods We integrated 278,337 cells from three single-cell RNA sequencing (scRNA-seq) datasets with bulk transcriptomic cohorts. Malignant-cell programs were mapped at single-cell resolution. Weighted gene co-expression network analysis (WGCNA) identified IFNG-associated modules, and ConsensusClusterPlus defined UPR-related patient clusters. Random Survival Forest and CoxBoost were then used to select prognostic genes. Results Lipopolysaccharide-binding protein (LBP) emerged as the top-ranked prognostic marker for LIHC. In GSE116174, GSE144269, and GSE14520, high LBP expression was associated with poorer overall survival. LBP also correlated with immune-cell infiltration, tumor microenvironment scores, immune modulators, and ICB-response determinants. Across public immunotherapy datasets, LBP showed response-classification value. In vitro , LBP knockdown reduced LIHC cell proliferation. Conclusions This study identifies LBP as a UPR-related and IFNG-associated candidate biomarker for LIHC prognosis and immunotherapy-response stratification. These findings support further preclinical and clinical validation of LBP in liver cancer.