Background
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), yet reliable biomarkers for early detection and risk stratification remain limited. This study aimed to identify plasma proteins associated with disease progression from chronic HBV infection to HCC.

Methods
Plasma proteomic profiling was conducted using high-resolution LC–MS/MS on samples from healthy controls, chronic HBV carriers, patients with cirrhosis, and individuals with HBV-associated HCC. Differentially expressed proteins were identified through bioinformatics analysis, and protein–protein interaction networks were reconstructed to assess functional relevance.

Results
Eight proteins displayed distinct, stage-specific expression patterns along the disease continuum. ICAM1, TIMP1, and IGFBP7 were progressively upregulated, reflecting roles in inflammation, fibrosis, and tumorigenesis. In contrast, PF4V1 and GPLD1 were downregulated, suggesting loss of protective functions during disease progression. PFN1, TUBA1B, and MDH1 exhibited dynamic modulation linked to cytoskeletal remodeling, cell division, and metabolic reprogramming. Network analysis revealed their involvement in pathways critical for immune regulation, extracellular matrix remodeling, and angiogenesis. Random forest modeling further confirmed their strong discriminatory potential for disease staging.

Conclusion
This study identifies a panel of plasma proteins closely associated with HBV-related HCC progression. These biomarkers may facilitate early detection, improve risk stratification in HBV-infected individuals, and provide new insights into the molecular mechanisms driving liver cancer development.

Hepatocellular carcinoma; Chronic hepatitis B; Cirrhosis; Plasma; proteomics; Biomarkers; Early detection