Metabolic reprogramming in hepatocellular carcinoma and its role in therapeutic resistance and intervention

Hepatocellular carcinoma (HCC) is a highly prevalent malignancy with poor prognosis, and therapeutic resistance remains a major barrier to improving patient survival. Metabolic reprogramming reshapes glucose, lipid, and amino acid metabolic networks, driving malignant proliferation and tumor progression. It also plays a critical role in the development of multiple resistance mechanisms. This review takes metabolic pathways as the organizing framework and systematically examines the reprogramming features of three major metabolic pathways and their association with therapeutic resistance. First, we outline the key features of metabolic alterations in three major pathways and highlight the interactions among these pathways and their cooperative roles in therapeutic resistance. Second, we summarize how metabolic reprogramming directly or indirectly regulates tumor immune–related mechanisms. Finally, we discuss metabolism-based therapeutic strategies, including targeting key metabolic nodes with single agents, combination approaches with immunotherapy or targeted therapy, and emerging interdisciplinary technologies integrating medicine and engineering. By systematically linking metabolic features to the underlying mechanisms of therapeutic resistance, this review aims to establish a conceptual framework connecting metabolic reprogramming with treatment resistance and provide a theoretical basis for developing precision therapeutic strategies.