Primary liver cancer (PLC), commonly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with a dismal prognosis. Recent research has highlighted the crucial role of dysregulation of fatty acid metabolism in HCC progression and therapeutic resistance. Here, with a focus primarily on HCC, we review how alterations in the processes involving fatty acids dynamically contribute to the survival, proliferation, and development of the drug resistance of PLC cells. In particular, increased expression of fatty acid transporters, reprogramming of de novo lipogenesis, and altered fatty acid oxidation trigger the upregulation of oncogenic signaling pathways and adaptation to nutrient-deprived conditions inducing the rapid proliferation of PLC cells. Furthermore, fatty acid metabolism influences immune cell function and angiogenesis, thereby shaping the tumor microenvironment and promoting the progression of PLC. This review explores the complex relationship between fatty acid metabolism and the progression of PLC. It discusses future directions regarding the most promising druggable targets and their current status in clinical trials. Furthermore, it examines the advancement of innovative therapeutic strategies and highlights the significant challenges in targeting fatty acid metabolism. Finally, it discusses how precision therapies focused on fatty acid metabolism can be effectively integrated with current treatments.
Cigliano et al. (2026) studied this question.