Metabolome Profiling of Malignant Ascites Identifies Candidate Metabolic Biomarkers of Hepatocellular Carcinoma

Background: Malignant ascites is one of the severe complications of hepatocellular carcinoma, which can be regarded as a unique tumor microenvironment of hepatocellular carcinoma. The identification of novel biomarkers in malignant ascites could be crucial to differentiate patients with hepatocellular carcinoma and cirrhotic ascites. Objective: The study aimed to distinguish the metabolomics of malignant ascites in patients with hepatocellular carcinoma from that of non-malignant ascites (cirrhotic ascites). Method: Liquid chromatography-mass spectrometry was used to analyze the differentially distributed biomarkers in patients with malignant ascites and hepatocellular carcinoma (n = 39), as well as in patients with benign and cirrhotic ascites, who were taken as healthy controls (n = 36). Results: A total of 20 differential metabolites associated with malignant ascites were identified, of which 8 metabolites were upregulated and 12 metabolites were downregulated (ratio < 0.5 or > 1.5, respectively). Moreover, pathway and enrichment analyses revealed nitrogen metabolism, urea cycle, phenylalanine, and tyrosine metabolism to be implicated in the formation of malignant ascites in patients with hepatocellular carcinoma. Conclusion: Our results suggest that the key factors associated with pathways, such as arachidonic acid, phenylalanine, and glutamic acid pathways, are potential ascitic fluid-based biomarkers for differentiating hepatocellular carcinoma with cirrhosis ascites; the results also provide a clinical pathophysiological interpretation of biomarkers and metabolic pathways relevant to disease status.