Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor that affecting many people's lives globally. The common risk factors for HCC include being overweight and obese. The liver is the center of lipid metabolism, synthesizing most cholesterol and fatty acids. Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment. Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors. Here, we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC. HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.

Keywords: Drug resistance; Hepatocellular carcinoma; Immunotherapy; Lipid metabolism; Targeted therapy; Therapeutic efficacy.

Figure 1

Fatty acid metabolism in hepatocellular carcinoma. A: Fatty acid metabolic pathway diagram; B: Changes of fatty acid metabolism in hepatocellular carcinoma and related targets. ACC: Acetyl- CoA carboxylase; ACLY: ATP citrate lyase; ACOX: Acyl-CoA oxidase 1; ACS: Acyl-CoA synthetases; CPT: Carnitine palmitoyl transfer; FASN: Fatty acid synthase; FA-CoA: Fatty Acyl-CoA; FFA: Free fatty acids; MCD: Malonyl-CoA decarboxylase; MUFA: Monounsaturated fatty acid; PPARα: Peroxisome proliferator-activated receptor α; TAC circle: Tricarboxylic acid cycle; SCD: Stearoyl-CoA desaturase; SIRT5: Sirtuin5; SREBP1c: Sterol-regulatory element binding protein 1c.

Figure 2

Cholesterol metabolism in hepatocellular carcinoma. A: Cholesterol metabolic pathway diagram; B: Changes of cholesterol metabolism in hepatocellular carcinoma and related targets. ABCA: ATP binding cassette subfamily A; ACAT1: Acyl-CoA cholesterol acyltransferase 1; CEs: Cholesterol esters; Farnesyl PP: Farnesyl diphosphate; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS: 3-hydroxy-3-methylglutaryl-CoA synthase; HSP90: Heat shock protein 90; LDLR: Low-density lipoprotein receptor; LXR: Liver X receptor; mSREBP2: Mature sterol regulatory element binding protein 2; PI3K: Phosphatidylinositol-3-kinase; PTEN: Phosphatase and tensin homolog deleted on Chromosome 10; SQLE: Squalene epoxidase; XBP-u: The unspliced X-box binding protein 1.