Abstract
Liver cancer, with hepatocellular carcinoma (HCC) as its predominant form, remains among the deadliest malignancies worldwide. Despite the expanding array of treatment options, current therapies benefit only a limited subset of patients. Metabolic reprogramming is a hallmark of cancer, with lipid metabolism playing a pivotal role in tumor progression, metastasis, and therapy resistance. HCC is profoundly influenced by alterations in lipid metabolic pathways, notably those involved in steatotic liver disease, a major risk factor. Key aspects such as de novo lipogenesis, lipid uptake, fatty acid oxidation, lipid peroxidation, biosynthesis of bioactive lipids, and cholesterol biosynthesis are all reprogrammed in liver cancer cells. These metabolic shifts modify the cancer cell lipidome-altering fatty acid unsaturation levels and other lipid profiles-to promote survival and resistance during therapy. Recent technological advances have deepened our understanding of dysregulated lipid metabolism in HCC. In this review, we examine how various facets of lipid metabolism contribute to HCC disease progression and resistance to standard treatments, including tyrosine kinase inhibitors, immune checkpoint inhibitors, and radiotherapy. We also explore the potential of targeting lipid metabolic pathways to enhance therapeutic efficacy and overcome resistance, highlighting dietary interventions as a promising, low-cost, low-side-effect strategy to resensitize resistant HCC cells.