Differential Metabolic Dysregulations in Hepatocellular Carcinoma and Cirrhosis: Insights into Lipidomic Signatures

Hepatocellular carcinoma (HCC), the most common primary liver malignancy, usually develops in patients with cirrhosis, yet the metabolic mechanisms that distinguish the two conditions remain poorly understood. This study aimed to explore metabolic dysregulations in HCC compared with cirrhosis and to identify potential biomarkers, especially lipids, with diagnostic and prognostic value. We prospectively studied 81 patients-41 with HCC and 40 with cirrhosis-using high-resolution UHPLC-QTOF-ESI⁺-MS to characterize their serum lipidome. Across both groups, 322 metabolites were identified, but their distribution was strikingly different. Patients with HCC showed higher levels of sphingolipids, glycerophospholipids, diglycerides, sterols, and certain fatty acids, reflecting tumor-related metabolic rewiring. In contrast, cirrhotic patients had increased D-glucose, 5-hydroxymethyluracil, lysophospholipids, acylcarnitines, and specific fatty acid derivatives. Several lipids, such as CerPE(d16:2/24:1(2OH)), SM(d18:0/14:0), PA(36:6), and GlcCer(d18:1/12:0), displayed excellent discriminative accuracy, highlighting their role as putative biomarkers. These findings underscore the importance of lipid metabolic reprogramming in HCC, characterized by membrane remodeling, energy adaptation, and oxidative stress resistance. Integrating lipidomic profiling into clinical practice could improve early detection and risk stratification in cirrhotic patients. Larger, multicenter studies are needed to validate these biomarkers and assess their therapeutic implications.