Abstract
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 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.