Novel Strategies against Hepatocellular Carcinoma through Lipid Metabolism

Hepatocellular carcinoma (HCC) is characterized by its highly invasive and metastatic potential, as well as a propensity for recurrence, contributing to treatment failure and increased mortality. Under physiological conditions, the liver maintains a balance in lipid biosynthesis, degradation, storage, and transport. HCC exhibits dysregulated lipid metabolism, driving tumor progression and therapeutic resistance. This review aims to elucidate the roles of fatty acid, sphingolipid, and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways. Key findings demonstrate that upregulated enzymes like fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), enhance <i>de novo</i> lipogenesis and β-oxidation, and promote HCC proliferation, invasion, and apoptosis evasion. Sphingolipids exert dual functions: ceramides suppress tumors, while sphingosine-1-phosphate (S1P) drives oncogenic signaling. Aberrant cholesterol metabolism, mediated by HMG-CoA reductase (HMGCR), liver X receptor α (LXRα), and sterol regulatory element-binding protein 1 (SREBP1), contributes to immunosuppression and drug resistance. Notably, inducing ferroptosis by disrupting lipid homeostasis represents a promising approach. Pharmacological inhibition of key nodes-such as FASN (Orlistat, TVB-3664), sphingomyelin synthase (D609), or cholesterol synthesis (statins, Genkwadaphnin)-synergizes with sorafenib/lenvatinib and overcomes resistance. We conclude that targeting lipid metabolic reprogramming, alone or combined with conventional therapies, offers significant potential for novel HCC treatment strategies. Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.