Table 1.

Preclinical practices of drugs in combination with sorafenib in HCC.

Drug	Target	Effect of the drug	Reference
Hypoxia inhibitors
EF24	HIF-1α	promoting VHL-dependent HIF-1α degradation and NF-κB inactivation	[20]
PT-2385	HIF-2α	suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways.	[25]
ICI-118551	ADRB2	inhibiting ADRB2 signaling and enhancing autophagic HIF1α degradation	[21]
Meloxicam	COX2	promoting VHL-dependent HIF-2α degradation, and inhibiting HIF-2α nuclear translocation	[18]
Celecoxib
2-ME2	HIF-1α	reducing the expression of both HIF-1α and HIF-2α	[19]
	HIF-2α
Melatonin	HIF-1α	inhibiting mTORC1/HIF-1α and hypoxia-mediated mitophagy	[72]
Stemness inhibitors
ATRA	AKT	reducing the EpCAM+ tumor cell population	[9]
Nifuroxazide	STAT3	blocking activation of STAT3 and expression of CD133 and HIF-1α proteins	[22]
ASC-J9	AR	blocking activation of STAT3	[26]
SSI-4	SCD1	inducing ER stress and suppressing liver CSCs	[76]
Tumor microenvironment modulators
AMD3100	CXCR4	reducing Gr-1(+) myeloid cell infiltration	[30,36]
Zoledronic acid	TAMs	depletion of macrophages and inhibiting tumor angiogenesis	[31]
Clodrolip
Anti-Ly6G	TANs	depletion of TANs and inhibiting neovascularization	[32]
Metabolic modulators
Etomoxir	CPT1	inhibition of FAO in liver CSCs	[13]
2-DG	G6P	reducing glucose uptake and cellular ATP levels	[41,43,62]
Aspirin 3PO	PFKFB3	inhibition of PFKFB3 and glycolysis	[44]
PB2	PKM2	suppressing glucose uptake and aerobic glycolysis	[45]
DCA	PDK	reducing lactate production and increasing ROS	[60]
3BP	HK2	inhibiting glycolysis	[46]
A-769662 FCCP	AMPK	Activating AMPK and decreased the expression of stemness markers	[50,53]
Ketoconazole	COX2	promoting mitophagy and mitochondrial dysfunction	[52]
BPTES	GLS1	inhibiting glutaminolysis	[62]
10058-F4	c-Myc	inhibiting c-Myc	[62]
ND-654	ACC1	inhibiting hepatic DNL	[75]
Oxidative stress inducers
Alkaloid trigonelline	NRF2	inducing ferroptosis	[64]
ATRA PPG	MT1G	increasing GSH depletion and ferroptosis	[65]
OT	TKT	increasing ROS accumulation	[66]
MTX	Folate	inhibition of the folate cycle	[67]
AUR	TXNRD1	increasing ROS accumulation	[68]
Ponatinib	FGFR4	enhancing ROS-associated apoptosis	[69]
Epigenetic modulators
5-AZA	-	demethylation of DNA	[78]
Panobinostat	HDAC	increasing histone H3 and HSP90 acetylation	[79]
Others
DR	KRAS	suppressing RAF/ERK and PI3K/AKT signaling	[83]

Abbreviations: 2-ME2, 2-Methoxyestradiol; ATRA, all-trans retinoic acid; 2-DG, 2-deoxy-d-glucose; 3PO, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; PB2, proanthocyanidin B2; DCA, dichloroacetate; 3BP, 3-bromopyruvate; FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; PPG, propargylglycine; OT, oxythiamine; MTX, methotrexate; AUR, auranofin; 5-AZA, 5-azacytidine; DR, Deltarasin.