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Cheng et al. Advances in liver fibrosis

safety profile in a phase I study in NASH patients β1-inducible focal adhesion protein, facilitates cell
with advanced fibrosis and is now under investigation proliferation, ECM expansion and vascular restoration
in patients with NASH cirrhosis (ClinicalTrials.gov and restructuring. [141] Hic-5 expression also plays a
Identifier NCT01899859 and NCT02462967; Table 3). critical role in attenuating fibrosis by enhancing TGF-
The pharmaceutical company is going to present the β1-induced small mother against decapentaplegic
data from this Phase 2 clinical trial by early December (Smad)2 phosphorylation via the downregulation of
2017. [134] Smad7 in both human and mouse activated HSCs. [142]

Other liver diseases Although several drugs show potent anti-fibrotic
Ursodeoxycholic acid (UDCA) was found to reduced activities in experimental models of hepatic fibrosis,
serum ALT, GGT and PIIIP in an early study. [135] there is presently no effective pharmaceutical
Candesartan, an angiotensin receptor blocking agent, intervention specifically approved for the treatment
together with UDCA, when compared to UDCA alone of liver fibrosis. Targeted delivery systems that bind
for 6 months, induced more significant improvement of specifically to receptors solely expressed on activated
fibrosis in histological and quantitative measurements HSCs or trans-differentiated MFBs are essential
in patient with compensated alcoholic liver disease. [136] to increase treatment efficacy as well as to reduce
UDCA combined with budesonide, but not UCDA adverse effects. The applicability and efficacy of
alone, led to fibrosis regression in patients with primary sequestering molecules, selective protein carriers,
biliary cholangitis (PBC, previously known as primary lipid-based drug vehicles, viral vectors, transcriptional
biliary cirrhosis). Obeticholic acid (OCA) is a semi- targeting approaches, therapeutic liver- and HSC-
synthetic 6-ethyl analogue of the endogenous bile acid specific nanoparticles, and miRNA-based strategies
chenodeoxycholic acid (CDCA) that is 100 times more are potential and promising treatment strategies. [143]
potent than CDCA as a Farnesoid X receptor (FXR)
activator. OCA has been shown to have anticholestatic, Collagen synthesis inhibitors
anti-inflammatory and antifibrotic effects. [137] OCA is Continuous accumulation of extracellular matrix (ECM)
found to be effective to improve liver biochemistries in extremely rich in collagen I and III in response to liver
a Phase 3 trial. [138] injury leads to scar deposition and liver fibrosis. [144]
Activated HSCs are indeed a major source of collagen
Specific anti-fibrotic treatment targets in the liver and can abundantly secrete ECM proteins,
Direct downregulation of hepatic stellate cell tissue inhibitors of metalloproteinases, and matrix
Hepatic stellate cells (HSC) are the main collagen- metalloproteinases (MMPs) that elicit liver architecture
producing cells in the liver and their activation promotes remodeling. [145] Apart from modulating HSC, there are
liver fibrosis. Targeting HSC is a popular strategy for some therapeutic agents directly targeting collagen
treating liver fibrosis. [139] Liver fibrosis can be reversed synthesis.
via a few mechanisms, which include inhibition of HSC
activation; promotion of HSC phenotypic conversion; Halofuginone is an analog of febrifugine - an alkaloid
immune clearance of HSC; promotion of HSC originally isolated from the plant Dichroa febrifuga. [146]
apoptosis; induction HSC senescence. [140] Several Animal model with established liver fibrosis
drugs have been tested to down-regulating HSC halofuginone elicited reductions in the levels of
activation, which include a few antioxidants (e.g. namely collagen, collagen αI gene expression, and α-smooth-
vitamin E, phosphatidylcholine, silymarin, resveratrol), muscle-positive cells, and even complete resolution of
gamma interferon, peroxisome proliferator-activated liver fibrosis. [147] Regeneration of the liver, which was
receptor gamma (PPAR-γ) agonists (e.g. pioglitazone), blocked in rats with established fibrosis, occurred at
endothelin receptor antagonists, histone deacetylase an almost normal rate in halofuginone-treated rats. [148]
(HDAC) inhibitors etc. [139] Yet none of these agents has Nonetheless, there has not been a clinical study
been approved as anti-fibrotic agents. specifically that use halofuginone to treat liver fibrosis
in human.
Several novel targets have been identified for the
treatment of liver fibrosis through suppression of TGF-β antagonists
HSC activation. Interleukin (IL)-30 attenuates hepatic TGF-β1 is the key pro-fibrogenic cytokine involved
fibrosis by inducing natural killer group 2D (NKG2D)/ in liver fibrosis, as it regulates the production and
ribonucleic acid export 1 crosstalk between activated deposition of ECM. [149,150] There are several approaches
HSCs and natural killer T cells and is therefore an ideal to interfere with TGF-β signaling. TGF-β expression
therapy for liver fibrosis. Hydrogen peroxide-inducible can be down-regulated by applying anti-sense
clone-5 (Hic-5), a transforming growth factor (TGF)- oligonucleotide mRNA. A targeted blocking of a specific

Hepatoma Research ¦ Volume 3 ¦ August 08, 2017 163