Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options:An Update

morbidity and mortality for healthcare systems worldwide.It imparts an enormous economic burden to societies,making continuous research and informational updates about its pathogenesis and treatment crucial.This review′s focus is on the current knowledge about the Wnt signaling path-way,serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells(HSCs).Two types of Wnt pathways are distinguished,namely the ß-catenin-dependent canonical and non-canonical Ca^(2+) or planar cell polarity(PCP)-dependent pathway.The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries.Activation of theß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix(ECM),leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes,lacking the original function of healthy hepatocytes.Therefore,liver function is reduced due to the severely advanced disease.Selective inhibition ofß-catenin inhibits inflammatory processes(since chemokines and pro-inflammatory cytokines are produced during Wnt activation),reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis,thereby reducing the progression of liver fibrosis in vivo.While the canonical Wnt pathway is usually inactive in a physiologically healthy liver,it shows activity during cell regeneration or renewal and in certain pathophysiological conditions,such as liver diseases and cancer.Targeted blocking of some of the basic components of the Wnt path-way is a therapeutic approach.These include the frizzled transmembrane receptor(Fz)receptors using the secreted frizzled-related protein family(sFRP),Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1(DKK1)or niclosamide,glycogen kinase-3 beta(GSK-3β)using SB-216763,cyclic-AMP response element-binding protein(CBP)using PRI-724 and ICG-001,the lymphoid enhancer binding factor(LEF)/T cell-specific transcription factor(TCF)system as well as Wnt inhibitory factor 1(WIF1)and miR-17-5p using pinostilbene hydrate(PSH).Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action.Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies’development.

An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents

Liver fibrosis represents a response to chronic liver injury.Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases,both with increasing incidence.Therefore,there is a great impetus for development of agents targeting these conditions.Accumulating data on possible treatment options for liver fibrosis are emerging in the literature.However,despite extensive research and much effort in the field,approved agents for liver fibrosis are still lacking.In this critical review,we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials,with an emphasis on efficacy and safety of these agents.

Drug-induced Fatty Liver Disease:Pathogenesis and Treatment

Metabolic dysfunction-associated fatty liver disease(commonly known as MAFLD)impacts global health in epidemic proportions,and the resulting morbidity,mortality and economic burden is enormous.While much attention has been given to metabolic syndrome and obesity as offending factors,a growing incidence of polypharmacy,especially in the elderly,has greatly increased the risk of drug-induced liver injury(DILI)in general,and drug-induced fatty liver disease(DIFLD)in particular.This review focuses on the contribution of DIFLD to DILI in terms of epidemiology,pathophysiology,the most common drugs associated with DIFLD,and treatment strategies.