Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Table 1 Novel intrahepatic targets explored by recent basic study

Molecular target	Potential agent	Classification	Function	Effects on NAFLD	Ref.
SREBPs	25-HL	Inhibitor	Decrease TG and cholesterol synthesis	-Hepatic steatosis	[10]
				-Liver inflammation
				-Liver fibrosis
ORM2	Recombinant ORM2; ORM2-FC fusion protein	Recombinant protein	Inhibit lipogenesis	-Hepatic steatosis	[11]
				-Liver inflammation
				-Liver fibrosis
Slc25al	CTPI-2	Inhibitor	Regulating cytoplasmic and mitochondrial citrate pool	-Hepatic steatosis	[12]
				-Liver inflammation
ACLY	Bempedoic acid	Inhibitor	Inhibit ACLY activity	-Hepatic steatosis	[14]
				-Liver injury
SHMT1/2	SHIN2 IV	Inhibitor	Decrease serine catabolism derived NADPH	-Hepatic lipogenesis	[16]
PCAF	Embelin	Inhibitor	Inhibit acetylation of LDHB	-Hepatic steatosis	[17]
				-Liver inflammation
Ketohexokinase	PF-06835919	Inhibitor	Regulating fructose metabolism	-Fructose-induced liver steatosis	[18]
Mitochondrial uncoupling	Sorafenib	Small molecule	Induce mitochondrial uncoupling and activate AMPK	-Hepatic steatosis	[21]
				-Liver inflammation
				-Liver fibrosis
				-NASH-associated HCC
MCJ	LNP-siMCJ; GalNAc-siMCJ	Nucleic acid-based therapy	Maintain mitochondrial function	+β-oxidation	[20]
				-Hepatic steatosis
				-Liver fibrosis
Cyclophilin D	CsA	Inhibitor		-Hepatic steatosis	[22]
ClpP	A54556A	Activator		-Hepatic steatosis	[42]
				-Liver inflammation
				-Liver fibrosis
SAB	GalNAc-Sab ASO	Nucleic acid-based therapy		-Hepatic steatosis	[43]
				-Liver inflammation
				-Liver fibrosis
ACMSD	TES-991	Inhibitor		-Hepatic steatosis	[45]
				-Liver inflammation
FOXA3	FOXA3 siRNA	Nucleic acid-based therapy	Attenuate ER stress induced liver steatosis	-Hepatic steatosis	[23]
TRIM5-DDX5	Hyperforcinol K	N/A	Inhibit ubiquitinated degradation of DDX5	-Hepatic steatosis	[24]
				-Liver inflammation
STK25	STK25 ASO	Nucleic acid-based therapy	Regulating energy homeostasis	-Hepatic steatosis	[28]
				-Liver inflammation
				-Liver fibrosis
RORa	RS-2982	Agonist	Increase miR-122 level	-Hepatic steatosis	[30]
				-Liver inflammation
				-Liver fibrosis
HSD17B13	Reproterol	Small molecule	Induce the Ser33 phosphorylation of 17β-HSD13 protein	-Hepatic steatosis	[38]
				-Liver fibrosis
PSD3	GalNAc-Psd3 ASO	Nucleic acid-based therapy	Decrease TG synthesis	-Hepatic steatosis	[39]
				-Liver injury
				-Liver fibrosis
Nrf2	TBE-31; NK-252; Dimethyl fumarate	Activator	Reduce oxidative stress	-Hepatic steatosis	[51-53]
				-Liver inflammation
				-Liver fibrosis
BCL-2	A22	Small molecule	Anti-apoptosis	-Liver injury	[54]
				-Liver fibrosis
RIPK1	RIPA-56	Inhibitor	Abrogating necroptosis	-Hepatic steatosis	[56]
				-Liver inflammation
CXCR2	AZD5069	Inhibitor	Inhibit neutrophil infiltration	-Hepatic steatosis	[63,65]
				-Liver inflammation
				-Liver fibrosis
				-NASH-associated HCC
MSR1	Anti-MSR1 antibody	Neutralizing antibody	Inhibit inflammatory response	-Hepatic steatosis	[67]
				-Liver inflammation
NLRP3	MCC950	Inhibitor	Inhibit NLRP3 activation	-Liver inflammation	[68]
				-Liver fibrosis
XBP1	Toyocamycin	Inhibitor		-Hepatic steatosis	[69]
				-Liver inflammation
				-Liver fibrosis
DCs	Curcumin; calcitriol	Small molecule	Shift hepatic DC inflammatory profile toward a regulatory phenotype	-Hepatic steatosis	[72]
				-Liver inflammation
				-Liver fibrosis
Hydrogen sulfide	NaHS	Hydrogen sulfide donor	Prevent the accumulation of TNF-α-producing CX3CR1+ moDCs	-Liver injury	[73]
TLR7	IRS-661	Antagonist	Decrease proinflammatory cytokine production in Kupffer cells and DCs	-Hepatic steatosis	[74]
				-Liver inflammation
Integrin	Anti-α4β7 antibody	Neutralizing antibody	Decrease α4β7+ CD4 T-cell recruitment	-Hepatic steatosis	[75]
				-Liver inflammation
				-Liver fibrosis
Tregs	Anti-CD25 antibodies	Neutralizing antibody	Deplete Tregs	-NASH-associated HCC	[76]
BAFF	Sandy-2	Neutralizing antibody	Prevent hepatic B2-cell responses	-Hepatic steatosis	[77]
				-Liver inflammation
				-Liver fibrosis
Notch	Nicastrin ASO	Nucleic acid-based therapy	Inhibit Notch signaling	-Liver fibrosis	[85]
	NP- dibenzazepine	Inhibitor with target delivery system		-Liver fibrosis	[88]
TAZ	GalNAc-TAZ siRNA	Nucleic acid-based therapy	Inhibit TAZ in hepatocyte and inhibit HSC activation	-Liver inflammation	[91]
				-Liver fibrosis
WISP1	Anti-WISP1 antibody	Neutralizing antibody	Inhibit HSC migration	-Liver fibrosis	[92]
IL-11	Anti-IL-11 antibody	Neutralizing antibody	Inhibit HSC activation; inhibit hepatocyte injury	-Liver injury	[93]
				-Liver fibrosis
JAK1/2	Ruxolitinib	Inhibitor	Inhibit HSC activation	-Liver fibrosis	[94]
JAK2	Pacritinib	Inhibitor	Inhibit HSC activation	-Liver fibrosis	[95]
STAT1	Rilpivirine	Inhibitor	Induce HSC apoptosis and promote hepatocyte proliferation	-Liver fibrosis	[96]
PAR2	Pepducin PZ-235	Antagonist	Inhibit HSC activation	-Liver injury	[97]
				-Liver fibrosis
VCAM-1	Anti-VCAM-1 antibody	Neutralizing antibody	Suppress monocyte adhesion to LSEC	-Liver inflammation	[101]
				-Liver fibrosis
eNOS	YC-1	Activator	Increase NO production from LSEC	-Hepatic steatosis	[102]
				-Liver inflammation
				-Liver fibrosis
Ltb4r1	CP-105696	Inhibitor	Inhibit the effects of LTB4	-Hepatic steatosis	[80]
				-Liver inflammation
				-Liver fibrosis
mPGES-2	SZ0232	Inhibitor	Regulating ARA metabolism	-Hepatic steatosis	[31]
CYP4A	TS-011	Inhibitor		-Hepatic steatosis	[32]
				-Liver inflammation
				-Liver fibrosis
N/A	Icosabutate	Structurally modified ω-3 fatty acid	Resist oxidation and activate free fatty acid receptor 4	-Liver inflammation	[84]
				-Liver fibrosis

-: Inhibit; +: Stimulate; SREBPs: Sterol regulatory element-binding proteins; TG: Triglyceride; 25-HL: 25-Hydroxanoanosterol; HSC: Hepatic stellate cell; LSEC: Liver sinusoidal endothelial cell; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; NO: Nitric oxide; N/A: No application; ORM2: Orosomucoid 2; ACLY: ATP-citrate lyase; SHMT1/2: Serine hydroxymethyltransferase 1/2; NADPH: Nicotinamide adenine dinucleotide phosphate; PCAF: P300/CBP-associated factor; LDHB: Lactate dehydrogenase B; AMPK: AMP-activated protein kinase; HCC: Hepatocellular carcinoma; MCJ: Methylation-controlled J; LNP: Lipid-nanoparticle-encapsulated; GalNAc: N-acetylgalactosamine; ClpP: Caseinolytic protease P; SAB: SH3 homology-associated BTK binding protein; ASO: Antisense oligonucleotides; ACMSD: α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase; FOXA3: Forkhead box A3; STK25: Sterile 20-type kinase serine/threonine kinase 25; RORa: Receptor-related orphan receptor alpha; PSD3: Pleckstrin and Sec7 domain-containing 3; Nrf2: Nuclear factor erythroid 2–related factor 2; RIPK1: Receptor-interacting protein kinase 1; CXCR2: CXC chemokine receptor 2; MSR1: Macrophage scavenger receptor 1; NLRP3: NOD-like receptor protein 3; XBP1: X-box binding protein-1; DC: Dendritic cell; TLR7: Toll-like receptor 7; Tregs: Regulatory T cells; BAFF: B-cell activating factor; NP: Nanoparticle-encapsulated; TAZ: Transcriptional co-activator with PDZ-binding motif; WISP1: WNT1-inducible signaling pathway protein 1; IL-11: Interleukin-11; JAK: Janus kinase; STAT1: Signal transducer and activator of transcription 1; PAR2: Protease-activated receptor-2; VCAM: Vascular cell adhesion molecule; eNOS: Endothelial nitric oxide synthase; LTB4: Leukotriene B4; mPGES: Microsomal prostaglandin E synthases; ARA: Arachidonic acid; CYP4A: Cytochrome P450 4A14; CsA: Cyclosporine A; TRIM5: Tripartite motif protein 5; DDX5: DEAD-box protein 5.

Table 2 Novel extrahepatic targets explored by recent basic study

Molecular target	Potential agent	Classification	Function	Effect	Ref.
AMPK	UO-Zn	Small molecule	Improve lipid metabolism	-Lipid accumulation in liver and circulation	[106]
BDK	BT2	Inhibitor	Regulating BCAA metabolism	-Hepatic steatosis	[107,108]
				-Liver inflammation
				-Liver fibrosis
HIF-2α (gut)	PT2385	Inhibitor	Decrease intestine-derived ceramide	-Hepatic steatosis	[112]
				-Liver injury
MYC (gut)	10058-F4	Inhibitor	Decrease intestine-derived ceramide	-Hepatic steatosis	[114]
				-Liver injury
				-Liver fibrosis
5-HT(gut)/HTR2A	Sarpogrelate	Antagonist	Inhibit gut-5-HT-liver Htr2α pathway	-Hepatic steatosis	[116]
PPARα (gut)	GW6471	Antagonist	Inhibit fatty acid absorption by intestine	-Hepatic steatosis	[117]
				-Liver inflammation
				-Liver fibrosis
MGAT2	BMS-963272	Inhibitor	Regulating fat absorption and liver TG synthesis	-Liver inflammation	[119]
				-Liver fibrosis
ISM1 (AT)	Recombinant Ism1	Recombinant protein	Suppress lipogenesis in liver	-Hepatic steatosis	[122]
				+Glucose tolerance
Sparcl1 (AT)	Anti-Sparcl1 antibody	Neutralizing antibody	Decrease CCL2 expression in liver	-Liver inflammation	[123]
				-Liver fibrosis
Gremlin 1 (AT)	Anti-Gremlin 1 antibody	Neutralizing antibody	Increase insulin sensitivity	-Insulin resistance	[124]
NRG4	hNRG4-Fc	Recombinant protein	Restrain the tumor-prone liver immune microenvironment	-NASH-associated HCC	[125]
SWELL1/LRRC8a (AT)	SN-401	Small molecule	Enhance insulin sensitivity and secretion	+Insulin sensitivity	[128]
				-Hepatic steatosis
				-Hepatocyte damage

AT: Adipose tissue; -: Inhibit; +: Stimulate; AMPK: AMP-activated protein kinase; BDK: Branched chain ketoacid dehydrogenase kinase; BCAA: Branched-chain amino acids; HIF-2α: Hypoxia-inducible factor 2α; MYC: Myelocytomatosis oncogene; 5-HT: 5-hydroxytryptamine; PPAR: Peroxisome proliferator-activated receptor; MGAT2: Monoacylglycerol acyltransferase 2; TG: Triglyceride; ISM1: Isthmin-1; Sparcl1: Secreted protein acidic and rich in cysteine-like protein 1; CCL2: C-C motif chemokine ligand 2; NRG4: Neuregulin 4; hNRG4-Fc: Human NRG4 and the Fc domain of immunoglobulin G 1; NASH: Nonalcoholic steatohepatitis; HCC: Hepatocellular carcinoma; UO: Ulvan oligosaccharide; BT2: 3,6-dichlorobrenzo(b)thiophene-2-carboxylic acid.