Review
Copyright ©The Author(s) 2023.
World J Gastroenterol. Jan 7, 2023; 29(1): 75-95
Published online Jan 7, 2023. doi: 10.3748/wjg.v29.i1.75
Table 1 Novel intrahepatic targets explored by recent basic study
Molecular target
Potential agent
Classification
Function
Effects on NAFLD
Ref.
SREBPs25-HLInhibitorDecrease TG and cholesterol synthesis-Hepatic steatosis [10]
-Liver inflammation
-Liver fibrosis
ORM2Recombinant ORM2; ORM2-FC fusion proteinRecombinant proteinInhibit lipogenesis-Hepatic steatosis[11]
-Liver inflammation
-Liver fibrosis
Slc25alCTPI-2InhibitorRegulating cytoplasmic and mitochondrial citrate pool-Hepatic steatosis[12]
-Liver inflammation
ACLYBempedoic acidInhibitorInhibit ACLY activity-Hepatic steatosis [14]
-Liver injury
SHMT1/2SHIN2 IVInhibitorDecrease serine catabolism derived NADPH-Hepatic lipogenesis[16]
PCAFEmbelinInhibitorInhibit acetylation of LDHB-Hepatic steatosis[17]
-Liver inflammation
KetohexokinasePF-06835919InhibitorRegulating fructose metabolism-Fructose-induced liver steatosis[18]
Mitochondrial uncouplingSorafenibSmall moleculeInduce mitochondrial uncoupling and activate AMPK-Hepatic steatosis[21]
-Liver inflammation
-Liver fibrosis
-NASH-associated HCC
MCJLNP-siMCJ; GalNAc-siMCJNucleic acid-based therapyMaintain mitochondrial function+β-oxidation[20]
-Hepatic steatosis
-Liver fibrosis
Cyclophilin DCsAInhibitor-Hepatic steatosis[22]
ClpPA54556AActivator-Hepatic steatosis[42]
-Liver inflammation
-Liver fibrosis
SABGalNAc-Sab ASONucleic acid-based therapy-Hepatic steatosis[43]
-Liver inflammation
-Liver fibrosis
ACMSDTES-991Inhibitor-Hepatic steatosis[45]
-Liver inflammation
FOXA3FOXA3 siRNANucleic acid-based therapyAttenuate ER stress induced liver steatosis-Hepatic steatosis[23]
TRIM5-DDX5Hyperforcinol KN/AInhibit ubiquitinated degradation of DDX5-Hepatic steatosis[24]
-Liver inflammation
STK25STK25 ASONucleic acid-based therapyRegulating energy homeostasis-Hepatic steatosis[28]
-Liver inflammation
-Liver fibrosis
RORaRS-2982AgonistIncrease miR-122 level-Hepatic steatosis[30]
-Liver inflammation
-Liver fibrosis
HSD17B13ReproterolSmall moleculeInduce the Ser33 phosphorylation of 17β-HSD13 protein-Hepatic steatosis[38]
-Liver fibrosis
PSD3GalNAc-Psd3 ASONucleic acid-based therapyDecrease TG synthesis-Hepatic steatosis[39]
-Liver injury
-Liver fibrosis
Nrf2TBE-31; NK-252; Dimethyl fumarateActivatorReduce oxidative stress-Hepatic steatosis[51-53]
-Liver inflammation
-Liver fibrosis
BCL-2A22Small moleculeAnti-apoptosis-Liver injury[54]
-Liver fibrosis
RIPK1RIPA-56InhibitorAbrogating necroptosis-Hepatic steatosis[56]
-Liver inflammation
CXCR2AZD5069InhibitorInhibit neutrophil infiltration-Hepatic steatosis[63,65]
-Liver inflammation
-Liver fibrosis
-NASH-associated HCC
MSR1Anti-MSR1 antibodyNeutralizing antibodyInhibit inflammatory response-Hepatic steatosis[67]
-Liver inflammation
NLRP3MCC950InhibitorInhibit NLRP3 activation-Liver inflammation[68]
-Liver fibrosis
XBP1ToyocamycinInhibitor-Hepatic steatosis[69]
-Liver inflammation
-Liver fibrosis
DCsCurcumin; calcitriolSmall moleculeShift hepatic DC inflammatory profile toward a regulatory phenotype-Hepatic steatosis[72]
-Liver inflammation
-Liver fibrosis
Hydrogen sulfideNaHSHydrogen sulfide donorPrevent the accumulation of TNF-α-producing CX3CR1+ moDCs-Liver injury[73]
TLR7IRS-661AntagonistDecrease proinflammatory cytokine production in Kupffer cells and DCs-Hepatic steatosis[74]
-Liver inflammation
IntegrinAnti-α4β7 antibodyNeutralizing antibodyDecrease α4β7+ CD4 T-cell recruitment-Hepatic steatosis[75]
-Liver inflammation
-Liver fibrosis
TregsAnti-CD25 antibodiesNeutralizing antibodyDeplete Tregs-NASH-associated HCC[76]
BAFFSandy-2Neutralizing antibodyPrevent hepatic B2-cell responses-Hepatic steatosis[77]
-Liver inflammation
-Liver fibrosis
NotchNicastrin ASONucleic acid-based therapyInhibit Notch signaling-Liver fibrosis[85]
NP- dibenzazepineInhibitor with target delivery system-Liver fibrosis[88]
TAZGalNAc-TAZ siRNANucleic acid-based therapyInhibit TAZ in hepatocyte and inhibit HSC activation-Liver inflammation[91]
-Liver fibrosis
WISP1Anti-WISP1 antibodyNeutralizing antibodyInhibit HSC migration-Liver fibrosis[92]
IL-11Anti-IL-11 antibodyNeutralizing antibodyInhibit HSC activation; inhibit hepatocyte injury-Liver injury[93]
-Liver fibrosis
JAK1/2RuxolitinibInhibitorInhibit HSC activation-Liver fibrosis[94]
JAK2PacritinibInhibitorInhibit HSC activation-Liver fibrosis[95]
STAT1RilpivirineInhibitorInduce HSC apoptosis and promote hepatocyte proliferation-Liver fibrosis[96]
PAR2Pepducin PZ-235AntagonistInhibit HSC activation-Liver injury[97]
-Liver fibrosis
VCAM-1Anti-VCAM-1 antibodyNeutralizing antibodySuppress monocyte adhesion to LSEC-Liver inflammation[101]
-Liver fibrosis
eNOSYC-1ActivatorIncrease NO production from LSEC-Hepatic steatosis[102]
-Liver inflammation
-Liver fibrosis
Ltb4r1CP-105696InhibitorInhibit the effects of LTB4-Hepatic steatosis[80]
-Liver inflammation
-Liver fibrosis
mPGES-2SZ0232InhibitorRegulating ARA metabolism-Hepatic steatosis[31]
CYP4ATS-011Inhibitor-Hepatic steatosis[32]
-Liver inflammation
-Liver fibrosis
N/AIcosabutateStructurally modified ω-3 fatty acidResist oxidation and activate free fatty acid receptor 4-Liver inflammation[84]
-Liver fibrosis
Table 2 Novel extrahepatic targets explored by recent basic study
Molecular target
Potential agent
Classification
Function
Effect
Ref.
AMPKUO-ZnSmall moleculeImprove lipid metabolism-Lipid accumulation in liver and circulation[106]
BDKBT2InhibitorRegulating BCAA metabolism-Hepatic steatosis[107,108]
-Liver inflammation
-Liver fibrosis
HIF-2α (gut)PT2385InhibitorDecrease intestine-derived ceramide-Hepatic steatosis[112]
-Liver injury
MYC (gut)10058-F4InhibitorDecrease intestine-derived ceramide-Hepatic steatosis[114]
-Liver injury
-Liver fibrosis
5-HT(gut)/HTR2ASarpogrelateAntagonistInhibit gut-5-HT-liver Htr2α pathway-Hepatic steatosis[116]
PPARα (gut)GW6471AntagonistInhibit fatty acid absorption by intestine-Hepatic steatosis[117]
-Liver inflammation
-Liver fibrosis
MGAT2BMS-963272InhibitorRegulating fat absorption and liver TG synthesis-Liver inflammation[119]
-Liver fibrosis
ISM1 (AT)Recombinant Ism1Recombinant proteinSuppress lipogenesis in liver-Hepatic steatosis[122]
+Glucose tolerance
Sparcl1 (AT)Anti-Sparcl1 antibodyNeutralizing antibodyDecrease CCL2 expression in liver-Liver inflammation[123]
-Liver fibrosis
Gremlin 1 (AT)Anti-Gremlin 1 antibodyNeutralizing antibodyIncrease insulin sensitivity-Insulin resistance[124]
NRG4hNRG4-FcRecombinant proteinRestrain the tumor-prone liver immune microenvironment-NASH-associated HCC[125]
SWELL1/LRRC8a (AT)SN-401Small moleculeEnhance insulin sensitivity and secretion+Insulin sensitivity[128]
-Hepatic steatosis
-Hepatocyte damage