Low-Abundance Serum Protein Biomarker Candidates for HCC in Patients with Liver Cirrhosis

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, often presenting diagnostic challenges in patients with underlying liver cirrhosis (CIRR). In this study, we employed both untargeted and targeted analysis of low-abundance serum proteins to identify potential biomarkers for HCC. In the untargeted study, we identified 15 proteins that exhibited statistically significant differential expression in HCC vs CIRR. In the targeted study, we confirmed differential expression of retinol-binding protein 4 (RBP4), dermcidin (DCD), bone morphogenetic protein 1 (BMP1), and putative sodium-coupled neutral amino acid transporter 10 (SLC38A10) by parallel reaction monitoring (PRM). Receiver operating characteristic (ROC) analysis highlighted the diagnostic potential of these proteins, demonstrating superior performance compared to alpha-fetoprotein. Functional enrichment analysis via gene ontology (GO) and ingenuity pathway analysis (IPA) identified key pathways implicated in HCC pathogenesis, including the liver X receptor/retinoid X receptor (LXR/RXR) pathway, immune regulation, extracellular matrix remodeling, and oxidative stress responses. Network analysis underscored HSPA5 and PPARG as critical hubs mediating interactions among dysregulated proteins, linking these to tumor progression and metabolic dysfunction. These findings provide novel insights into the molecular mechanisms of HCC and identify RBP4, DCD, BMP1, and SLC38A10 as promising biomarkers for HCC in patients with liver cirrhosis.