| Sumario: | Simple Summary: Hepatocellular carcinoma (HCC) remains a clinically important complication in a subset of patients even after sustained virological response (SVR) is achieved for hepatitis C virus infection, thus necessitating more accurate methods for identifying those at continued risk. This study was designed to determine whether serum metabolites measured before and after SVR could predict post-SVR HCC development. Methionine, methionine sulfoxide, and ornithine were identified as metabolites associated with subsequent HCC risk, and their combination with established clinical markers improved discrimination between low- and high-risk patients. These findings suggest the potential utility of metabolite-based risk stratification for post-SVR HCC and may contribute to more individualized surveillance strategies following SVR. Background: Abnormalities in energy and amino acid metabolism are potentially involved in hepatocellular carcinoma (HCC) development. This study aimed to identify serum metabolites predictive of HCC following sustained virological response (SVR) with hepatitis C virus (HCV) treatment. Methods: Comparative metabolomics was conducted using time-course serum samples from patients who failed interferon-based therapy but subsequently achieved SVR with direct-acting antivirals (DAAs), minimizing inter-individual variability. Predictive biomarkers for post-SVR HCC were extracted from the results and validated by comparing 29 patients who developed post-SVR HCC with 58 age-matched patients who remained HCC-free during follow-up. Results: Metabolite concentrations changed more markedly after treatment in SVR cases than in non-SVR cases. Significant changes in methionine (Met), methionine sulfoxide (MetO), and ornithine (Orn) levels before and after treatment (Pre- and Post-Tx) were found only in the non-HCC group. Regression and survival analyses identified high levels of Pre- and Post-Tx Orn, Pre-Tx Met, and Post-Tx MetO as predictors of post-SVR HCC and enabled risk stratification. The integration of these metabolites with the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) facilitated risk stratification and discriminated between high- and low-risk patients. The Pre-Tx FIB-4/Met model and the Post-Tx AFP/MetO/Orn model identified low- and high-risk groups with 3-year HCC incidence rates of 6.4% and 81.8%, respectively. Conclusions: Serum Met, MetO, and Orn were identified as candidate biomarkers associated with post-SVR HCC development, which remains a concern in the fight against hepatitis C. Combining these metabolites with established clinical markers may improve post-SVR HCC risk stratification.
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