Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Table 1 Impacts of lipid metabolism related reagents on the treatment of hepatocellular carcinoma

	Type of lipid metabolism	Reagents	Specific impact	Ref.
Targeted therapy	Fatty acid	SSI-4	Blocking SCD1, then enhancing the efficacy of sorafenib by regulating endoplasmic reticulum stress	[49]
		Orlistat	Improving sorafenib resistance by inhibiting FASN	[51]
		Brusatol	Inhibiting NRF2, then improving the efficacy of sorafenib by improving lipid metabolism disorder and promoting redox homeostasis	[54]
		Auranofin	Inhibiting TXNRD1, then improving the efficacy of sorafenib by improving lipid metabolism disorder and promoting redox homeostasis	[54]
		Etomoxir	Enhancing the efficacy of sorafenib by inhibiting mitochondrial fatty acid oxidation	[55]
		DHA	Enhancing the efficacy of sorafenib by improving 19,20-erythropoietic acid (19,20-EDP) level	[59]
		Sodium butyrate (NaBu)	Improving the curative effect of sorafenib by regulating the expression of hexokinase 2	[60]
		Betulin	Alleviating the adverse reaction of sorafenib and improving its efficacy by blocking SREBP-1	[62]
		TVB3664	Enhancing the efficacy of cabozantinib and sorafenib by inhibiting FASN	[18]
	Cholesterol	Simvastatin	Enhancing the efficacy of sorafenib by inhibiting cholesterol synthesis	[68-69]
		Maprotiline	Enhancing the efficacy of sorafenib by inhibiting cholesterol synthesis through reducing the phosphorylation level of SREBP2	[73]
		Emodin	Enhancing the efficacy of sorafenib by inhibiting cholesterol synthesis through inhibiting SREBP2	[74]
		Lycorine	Lowering the level of intracellular cholesterol by inhibiting SCAP, then enhancing the efficacy of sorafenib	[76-77]
		T0901317	Regulating cholesterol efflux by activating LXR, then enhancing the efficacy of sorafenib	[80]
		Caspase-3	Improve the drug resistance of HCC to lenvatinib by promoting the synthesis of cholesterol	[84]
	Other lipid metabolism	D609	Inhibiting SMS1, and then enhancing sorafenib efficacy by lowering Ras activity	[87]
		ABC294640	Reducing the formation of S1P by inhibiting SK2, then enhancing the efficacy of sorafenib	[88]
		Bavituximab	Enhancing the efficacy of sorafenib targeting tumor angiogenesis and reactivating antitumor immunity	[89]
Immunotherapy	Fatty acid	Perhexiline	Prolonging the survival of CD4+ T cell through inhibiting CPT	[103]
		Fenofibrate	Improving the efficacy of cancer vaccine through activating PPARα in other tumors (worth exploring in HCC)	[104]
	Cholesterol	Avasimibe	Enhancing the function of CD8+T cells by inhibiting ACAT1, thereby improving the therapeutic effect of PD-1 inhibitors (worth exploring in HCC)	[107]
		Simvastatin	Its combination with PD-L1 antibody effectively inhibits the proliferation of HCC	[111]

CPT: Carnitine palmitoyl transfer; FASN: Fatty acid synthase; LXRα: Liver X receptor α; PD-L1: Programmed death-ligand 1; PD-1: Programmed cell death protein 1; PPARα: Peroxisome proliferator-activated receptor α; NRF2: Nuclear factor E2 related factor 2; TXNRD1: Thioredoxin reductase 1; SCAP: The SREBP cleaning activating protein; SCD1: Stearoyl-CoA desaturase 1; SK2: Sphingosine kinase 2; SMS1: Sphingomyelin synthase1; SREBP: Sterol-regulatory element binding protein; S1: Sphingosine 1-phosphate; HCC: Hepatocellular carcinoma; DHA: Docosahexaenoic acid.