Cirrhosis severity modulates proteomic and immune landscapes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) most often arises in cirrhotic livers, yet the biological impact of cirrhosis severity on the tumor proteome remains poorly understood. We performed a quantitative proteomic analysis of 141 HCC tumors from a publicly available mass spectrometry dataset (Xing et al. Cell Reports Medicine, 2023), stratified by cirrhosis severity to delineate fibrosis-related molecular heterogeneity. Principal component analysis revealed substantial overlap between groups, indicating that increasing cirrhosis severity produces incremental rather than global proteomic shifts. Nevertheless, 295 proteins showed significant differential abundance (Hedges' g > 0.3, p < 0.05), including upregulation of HMOX1 and LRSAM1 and downregulation of CYP27A1 in Medium/High cirrhosis. Pathway enrichment highlighted alterations in organelle assembly, heme metabolism, and extracellular-matrix disassembly, alongside reduced cytoskeletal and focal-adhesion integrity. Exploratory immune deconvolution suggested proportional remodeling of natural-killer and B-cell subsets with advancing cirrhosis. A five-gene signature (HMOX1, LRSAM1, MAP2, EDEM3, RFC3) was associated with significantly worse overall survival in TCGA-LIHC (HR 1.8, p = 0.0021); cirrhosis severity alone did not predict survival (log-rank p = 0.248), supporting the tumor-intrinsic prognostic relevance of the signature. These findings demonstrate that cirrhosis severity subtly but measurably reshapes the HCC tumor proteome and immune landscape, with implications for risk stratification and precision therapy design.