Table 1.

The major drug targets for potential anti-fibrogenic drugs

Mode of action	Targeting	Potential therapeutic agents and comments
1 Preventing primary cause of disease		Undoubtedly, preventing or curing the primary cause of disease is the best way to prevent or treat liver fibrosis. Anti-fibrogenics are required when the primary cause of disease is not successfully treated.
2 Antioxidants	Reactive oxygen species released from inflammatory cells (also possibly myofibroblast proliferation).	N-acetyl cysteine [31, 32], resveratrol [32], quercetin [32]. Note, quercetin is also a WNT signalling inhibitor (Tcf/Lef inhibitor) [33] and a repression of WNT signalling has been associated with trans-differentiation to myofibroblasts [34, 35]. Vitamin E [36], evidence of anti-fibrogenic effects in patients with NASH treated with vitamins C and E [37]. Angiotensin II inhibitors—via inhibiting the activation of NADPH oxidase mediated by angiotensin II [38].
3 Anti-inflammatory agents	Glucocorticoid receptor	Glucocorticoid agonists often administered to inhibit inflammation, particularly in immune-mediated hepatitis [39]. May not have any direct effects on fibrosis [40] but dexamethasone has been noted to inhibit TGFβ expression in liver myofibroblasts in vitro [41]. Note, Kupffer cell-targeted glucocorticoids lead to increased levels of fibrosis in experimental animal models [42].
	Cyclooxygenase	Cyclooxygenase (COX) inhibitors inhibit the production of leukotrienes and prostaglandins, e.g. COX2 inhibitor JTE-522 [43]. However, hepatic COX2 knockout or overexpression in transgenic mice is reported to have no effects on liver fibrosis [44].
	NF-κB.	NF-κB inhibitors (e.g. sulfasalazine [45]). However, primary effects believed to be mediated via apoptosis (see 5).
4 Proliferation inhibitors	Peroxisome proliferator activated receptor-γ (PPARγ).	PPARγ agonists—such as anti-diabetic thiazolidones (e.g. troglitazone, rosiglitazone, pioglitazone—inhibit trans-differentiation/proliferation of myofibroblasts in vitro [46, 47]. PPARγ is expressed in hepatic stellate cells but falls rapidly in primary culture as the cells trans-differentiate to myofibroblasts [47].
		Farglitazar is completing an anti-fibrogenic trial in patients with chronic hepatitis C[1]. Curcumin effects may also function via PPAR γ [48].
	Farnesoid X receptor (FXR).	FXR activator synthetic bile acid INT-747 is anti-fibrogenic [8] although effects could also be mediated via PXR since this related receptor also ligands bile acids [49]. Currently undergoing clinical trial [1].
	Pregnane-X receptor (PXR).	PXR ligands (e.g. rifampicin, hyperforin) inhibit proliferation and ECM synthesis [50, 51]. Rifampicin is often given to patients with primary biliary cirrhosis (to control itch) and has been shown to reduce serum levels of alkaline phosphatase in patient trials [52, 53]. However, its effects on fibrosis have not been examined. Ursodeoxycholate is also a PXR activator [54]. This compound is also given to patients with primary biliary cirrhosis and has been reported to reduce progression to cirrhosis [55].
	Renin-angiotensin system	Liver myofibroblasts synthesise angiotensin, which acts in an autocrine manner to promote fibrosis [56]. Angiotensin II R1 antagonists (e.g. losartan) inhibit proliferation and also ECM synthesis [57] and have been reported to reduce fibrosis in clinical trails [58]. The angiotensin II R1 antagonist irbesartan is currently undergoing clinical trials [1]. Angiotensin-converting enzyme (ACE) inhibitors are also potential therapeutics, (e.g. perindopril [59]).
	Phosphodiesterase	Pentoxifylline has been shown to inhibit liver fibrosis in animal models [60, 61]. Pentoxifylline is an inhibitor of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate (cAMP) [62], but may act by other mechanisms [63]. Undergoing clinical trials for survival rate in patients with cirrhosis [1].
	MAP kinase	Salvianolic acid [64], but may have other targets [65]. Reported to inhibit fibrosis in a cohort of patients with hepatitis B [66].
	Unknown	Pirfenidone [67]. In relation to the mechanism of the anti-fibrotic action, pirfenidone has been shown to modify cytokine regulatory actions, inhibit fibroblast proliferation and collagen matrix synthesis. Shown to be effective in clinical trials [1]. Halofuginone inhibits myofibroblast proliferation by unknown mechanism [68, 69] and also by other mechanisms (see 6 and 8).
	CB1 receptor	CB1 receptor is expressed in myofibroblasts and promote fibrosis [70]. CB1 antagonism (e.g. via SR141716A/rimonabant) inhibits fibrosis [70], also increases myofibroblast apoptosis [70].
	CB2 receptor	CB2 receptor agonists (e.g. Δ9-tetrahydrocannabinol [71]). Note, however, that daily cannabis smoking is associated with fibrosis progression [72].
	Opioid receptor	Opioid receptor antagonists (e.g. naltrexone [73]).
	Serotonin (5HT) receptor	Rodent and human myofibroblasts express several 5HT receptor sub-types; 5HT2 antagonists are anti-fibrogenic (e.g. methiothepin maleate or spiperone [74]). Also increases myofibroblast apoptosis [74].
5 Pro-apoptotics	NF-κB	Through inhibition of activation via IKK inhibition (e.g. sulphasalazine [45]), also proteasomal inhibitors [75]. Note, human liver myofibroblasts may become more resistant to proteasomal inhibitors with time [76]. Gliotoxin inhibits NF-κB via proteasomal inhibition [12], however, it also targets mitochondria [45], which may explain its potency at stimulating human myofibroblast apoptosis [11, 76] and inhibition of fibrosis in vivo [11, 21].
	RS kinase	RS kinase inhibition promotes myofibroblast apoptosis and inhibits liver fibrosis in animal models [77].
	CB1 and CB2 receptors (see 4)
	5HT receptors (see 4)
6 ECM synthesis inhibitors	TGFβ	TGFβ antagonism (e.g. decoy soluble TGFβ receptor [78]), However, TGFβ may be critical for other tissues and may be a tumour supressor [79]. Inhibitors of proteolytic TGFβ activation (e.g. camostat mesilate [80]). Halofuginone [81].
7 Anti-protease inhibitors	Tissue inhibitors of metalloproteinases (TIMP).	Polaprezinc down regulates TIMP1 and 2 expression [82]. Antagonistic antibodies [83].
8 Pro-proteases		uPA via adenoviral gene therapy in animal model [84]. Halofuginone increases fibrolytic MMP expression [69, 85].

The table outlines some of the potential anti-fibrogenic drug targets for which potential therapeutic agents are already available. There are additional pathways for which either intervention remains unexploited or information is not freely available. These include intervening in adiponectin signalling, which suppresses PDGF-dependent myofibroblast proliferation and fibrosis in experimental animal models [86], and leptin, which is synthesised by myofibroblasts [87] and promotes fibrosis [88]