Table 4.
Anti-apoptotic, inflammatory, and fibrogenic agents in the preclinical stage
| Class | Targets | Drug name | Experimental models | Outcome | Ref. |
|---|---|---|---|---|---|
|
Cell death (target on apoptosis) |
ASK1 inhibitor | Peptide fragment of CFLAR [CFLAR(S1)] |
HFD-fed mouse model Pelleted primate HFD-fed monkey model with MetS predisposal |
↓Steatohepatitis ↓Metabolic disorders |
625 |
|
Overexpression of TNFAIP3 by adeno-associated virus 8 (AAV8)-TNFAIP3 injection |
HFD-fed mouse model HFHC diet-fed ob/ob mouse model Pelleted primate HFD-fed monkey model with MetS predisposal |
↓Lipid accumulation ↓Hepatic steatosis ↓Inflammation ↓Fibrosis |
325 | ||
| Glutathione S-transferase Mu 2 (GSTM2) | HFD-fed Gstm2-hepatocyte-specific knockout mouse model |
↓Insulin resistance ↓Hepatic steatosis ↓Gene expression related to lipid metabolism |
626 | ||
| Ferroptosis inhibitor | ECH1 | MCD diet-fed mouse model |
↓Hepatic steatosis, fibrogenesis ↓Inflammation ↓Apoptosis ↓Oxidative stress ↓ALT |
356 | |
| Cdk4 inhibitor | Flavopiridol or PD-0332991 | HFD-fed mouse model | ↓Hepatic steatosis | 453 | |
| Necroptosis inhibitor | TN3-19.12 | CD- and HFD-fed mice model |
↑RIP1, RIP3, and MLKL ↓ALT and AST ↓Liver injury ↓Hepatocyte necrosis |
336 | |
| Necrostatin-1 (Nec-1) | |||||
| GSK′872 | |||||
| Pyroptosis inhibitor | Cytochalasin B | Primary mouse and human hepatocytes |
↓IL-1ß and α-SMA ↓Inflammation and fibrosis |
344 | |
| Ghrelin | HepG2 cells | ↓TNF-α-induced apoptosis and hepatocyte autophagy | 345 | ||
|
Cell death (target on autophagy) |
ATG3 inhibitor | shRNA against ATG3 |
CDHFD, HFD, or MCD-fed mouse model TAp63α-induced mouse steatosis model |
↓ALT, AST ↓Steatosis |
326 |
| TXNIP agonist | Rapamycin | MCD diet-fed Txnip-KO mouse model |
↓Steatosis ↓Inflammation ↓Fibrosis ↓FAO |
330 | |
| Anti-inflammatory agents | Anti-TNF-α drug | Infliximab | MCD diet-fed rat model |
↓NASH histopathology score ↓AST, ALT ↓Fibrosis, TGF-β ↓Plasma and tissue MDA ↓Inflammation |
411,412 |
| Thalidomide | HFD-fed mouse model |
↓Blood glucose level ↓Liver TG content ↓Hepatic inflammatory markers |
413 | ||
| Hepatic macrophage polarization | Annexin A5 (ANXA5) | HFD-fed mouse model |
↓Steatosis ↓Inflammation ↓Fibrosis |
627 | |
| IL-11 antibody | Anti-IL-11 (X203), anti-IL11RA (X209) |
High-fat methionine and choline-deficient (HFMCD) diet-fed mouse model MCD diet-fed db/db mouse model Western diet supplemented with fructose (WDF)-fed mouse model |
↓Hepatic steatosis ↓Fibrosis ↓Inflammation |
402 | |
| TLR4 antagonist | Sparstolonin B (SsnB) | HFD-fed mouse model | ↓Liver fibrosis | 415 | |
| NLRP3 inhibitor | Sulforaphen (SFN) | HFD-fed mouse model |
↓Hepatic steatosis scores ↓Serum ALT and AST ↓Hepatic TC, TG ↓FFAs |
416,417 | |
| Erk1/2 inhibitor | FR180204 | MCD diet-fed mouse model |
↓ALT, AST ↓CHO, TG |
628 | |
| ERK antagonist | Ravoxertinib | MCD diet-fed mouse model |
↓ALT, AST ↓CHO, TG ↓Steatosis ↓Inflammatory state |
629 | |
| Antifibrosis | P53 activator | IGF-I |
MCD diet-fed db/db mouse model Dimethylnitrosamine-treated mouse model |
↓Steatosis ↓Inflammation ↓Fibrosis |
630 |
| Anti-TGF-β drug | Breviscapine | HFD, HFHC, or MCD diet-fed mouse model |
↓Lipid accumulation ↓Inflammatory cell infiltration ↓Liver injury and fibrosis |
448 | |
| SP-1154 | HFD-fed mouse model |
↓Inflammation ↑Insulin sensitivity, glucose homeostasis ↓Hepatic steatosis |
441 | ||
| Oxy210 | “Western” diet (WD)-fed mouse model |
↓Hepatic fibrosis ↓Inflammation ↓Hypercholesterolemia |
442 | ||
| TIPE2 | HFD or HFHC diet-fed hepatic Tipe2-transgenic mouse model |
↓Hepatic steatosis ↓Insulin resistance ↓Inflammation ↓Fibrosis |
446 | ||
| Tetrodecadazinone | TGF-β1-activated LX-2 cell model |
↓Expression of extracellular matrix proteins (fibronectin and collagen I) ↓α-SMA |
443 | ||
| Phosphodiesterase 4 (PDE4) inhibitor | Roflumilast | HFD-fed mouse model |
↓Hepatic steatosis ↓Liver weight and body weight ↓Circulating cholesterol (CHO) and LDL-C No effect on circulating HDL-C and TG |
631 | |
| Medicinal herbs | Yellow loosestrife (Lysimachia vulgaris var. davurica) | MCD diet-fed db/db mouse model |
↓Lipid accumulation ↓Inflammation ↑Antioxidative proteins |
444 | |
| Suppresses activation of HSCs | Emodin | HSC-T6 cell model |
↓Proliferation and activation of HSCs ↓TGFβ1/Smad signaling pathway in activated HSCs |
454,455 | |
| Overexpression of human HNF4α (hepatocyte nuclear factor 4α) | AAV8-ALB-hHNF4α | High-fat/cholesterol/fructose (HFCF) diet-fed mouse model |
↓Steatohepatitis ↓TG ↑FAO ↑VLDL secretion |
632 | |
| TAZ inhibitor | GalNAc-siTAZ | NASH diet-fed mouse model |
↓Hepatic inflammation ↓Liver injury ↓Fibrosis |
567 | |
| Notch inhibitor | GSI | NASH diet-fed mouse model |
↓HSC activation and liver fibrosis ↑Goblet cell metaplasia |
568 | |
| Ncst ASO | NASH diet-fed mouse model |
↓Fibrosis (expression of HSC markers and collagen deposition) No effect on serum transaminases and liver inflammation |
568 | ||
| Antioxidative stress agents | Antioxidative stress agents | Matrine | HFD or MCD diet-fed mouse model |
↓Hepatic inflammation ↓Lipid peroxides ↓ALT and AST ↓Fibrosis |
633,634 |
| Polaprezinc | MCD diet-fed mouse model |
↓Fibrosis ↓Lipid peroxidation ↓Inflammation No effect on the development of steatosis. |
635 | ||
| Genetic approaches | HSD17B13 inhibitor | INI-678 | Human cell “3D liver-on-a-chip” model (https://inipharm.com/) | ↓Markers of liver fibrosis (α-SMA, Col-I) | 562 |
| PNPLA3-rs738409 (I148M) variant inhibitor | Minor allele-specific small interfering RNA (siRNA) | NASH diet-fed PNPLA3I148M-expressing mouse model |
↓Hepatic TG ↓ALT ↓Histological assessment of inflammation |
636,637 | |
| PNPLA3 expression downregulator | Momelotinib | Human multilineage 3D spheroid model of NASH homozygous for the PNPLA3 mutant protein |
↓PNPLA3 mRNA ↓Lipid content |
638 | |
| Gut microbiota targets | Gut microbiota targets | Fecal microbiota transplantation (FMT) | HFD-fed mouse model |
↓Steatohepatitis ↓NAS score ↓Intrahepatic lipid accumulation ↓Proinflammatory cytokines |
531 |
| Adenosine A(2a) receptor agonists | CGS21680 | MCD diet-fed rat model |
↓ALT ↓Hepatocyte apoptosis ↓Liver inflammation ↓Fibrosis No effect on hepatic steatosis. |
639 | |
| Ras-association domain family 4 (RASSF4) agonists | Overexpression of RASSF4 | db/db genetic mouse model |
↓Hepatic steatosis ↓Inflammation levels ↓Fibrosis |
640 | |
| Target sphingomyelin synthase 1 (SMS1) | shRNA-mediated knockdown of Sms1 | HFHC diet-fed shRNA-mediated knockdown of Sms1mouse model |
↓Inflammation and fibrosis ↓TGFβ1, α-SMA ↓ALT No effect on hepatic TG |
641 |