Liver-specific propanoate metabolism-derived 2-ethylhexanol as a novel biomarker for precise diagnosis and prognosis of hepatocellular carcinoma.

Alterations in propanoate metabolism are increasingly recognized as significant biomarkers for various liver disorders, notably hepatocellular carcinoma (HCC). To enhance diagnostic specificity for HCC, we conducted integrated binary omics and targeted metabolomics analyses, identifying liver-specific propanoate metabolism (LPM) gene signatures and associated metabolites. Leveraging data from 40 tissues and 81 cell subclasses, hepatocytes showed the highest metabolic specificity. Clinical validation using the TCGA-LIHC cohort highlighted LPM genes, notably ALDH2 and ABAT, as robust prognostic markers significantly associated with poor survival outcomes. Serum metabolomic profiling of 273 patients demonstrated that elevated toluene and xylene isomers and significantly reduced 2-ethylhexanol distinctly characterize HCC, distinguishing it from liver cirrhosis, hepatitis, and other cancers. These findings emphasize the potential of LPM-based metabolic profiling as a precise diagnostic and prognostic tool, with potential implications in targeted therapeutic development for HCC.