Shared Molecular Features Between Primary Biliary Cholangitis and Hepatocellular Carcinoma Define a Prognostic Gene Signature for Risk Stratification

Background Primary Biliary Cholangitis (PBC) is an autoimmune liver disease that may progress to Hepatocellular Carcinoma (HCC) in a subset of patients. However, the molecular features shared between PBC and HCC remain largely unknown. This study aimed to identify common genes linking these diseases and to develop a prognostic model for HCC, with comprehensive analyses to support risk stratification and clinical decision-making. Methods Transcriptomic datasets from public repositories were integrated. Differential expression analysis, WGCNA, and survival analyses were conducted to identify the genes shared between PBC and HCC. Peripheral blood samples from patients with HCC and PBC were collected to validate the expression of key genes using RT-qPCR. A risk score (RS) model was constructed using LASSO regression and validated in an independent cohort. A nomogram combining RS and clinical variables was developed. Mutation profiles, immune infiltration, drug sensitivity, immunotherapy response, and pathway enrichment were systematically analyzed. Results Seven genes (MARCH1, ARHGAP4, MZB1, PLCH2, MMP9, SLC16A3, and ZNF341) were included in the RS model. RT-qPCR confirmed significant differential expression of these genes in peripheral blood samples, consistent with the transcriptomic results. The RS model demonstrated robust prognostic value in both the training and validation cohorts, and the nomogram exhibited strong predictive performance. Comparative analyses between the high- and low-risk groups revealed distinct immune cell compositions, mutation landscapes, drug sensitivity profiles, immunotherapy responsiveness, and pathway activities. Conclusions The seven-gene RS model and nomogram effectively stratified prognostic risk in PBC-associated HCC and highlighted potential molecular connections between these diseases, offering insights for personalized prognosis and therapeutic strategies.