This study aimed to identify and validate noninvasive serum protein and metabolite biomarkers for the early detection and prognostic assessment of hepatocellular carcinoma (HCC). In this study, we systematically analyzed serum proteomics and metabolomics across four cohorts, including healthy controls (Health) and patients with chronic hepatitis B (CHB), liver cirrhosis (LC), and HCC. Standardized sample handling protocols were applied, and high-resolution mass spectrometry combined with rigorous statistical analyses was used to identify differential proteins and metabolites.