Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.

Abstract

Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major cause of cancer-related mortality worldwide, with rising incidence and limited treatment options, especially for patients diagnosed at advanced stages. In recent years, metabolic reprogramming has emerged as a hallmark of cancer that enables HCC cells to survive, proliferate, and resist therapy under hostile conditions. HCC cells undergo profound remodeling of glucose, lipid, and amino acid metabolism to adapt to hypoxia and nutrient deprivation. These processes are orchestrated by key signaling cascades, including the PI3K/AKT/mTOR, Ras-Raf-MEK-ERK-cMYC, and LKB1-AMPK pathways, forming a dynamic and integrated metabolic-signaling network. This review comprehensively integrates recent advances in the understanding of metabolic pathways in HCC, with a particular focus on glycolysis, de novo lipogenesis, and glutamine metabolism. We delineate the regulatory mechanisms underlying these pathways and construct an interaction map linking metabolic circuits to clinical phenotypes such as tumor heterogeneity, metastatic potential, and immune modulation. Furthermore, we systematically evaluate the biomarker potential of metabolic intermediates, rate-limiting enzymes, and key regulators in the context of early detection, molecular classification, prognosis prediction, and therapeutic response in HCC. We also highlight cutting-edge technologies, including metabolic imaging, liquid biopsy-based biomarker detection, and metabolism-targeted therapies. The review explores their potential synergy with immunotherapy, chemotherapy, and radiotherapy, aiming to provide a comprehensive framework for individualized HCC management. Our discussion underscores the translational relevance of metabolic biomarkers and offers insights for future research and clinical innovation.