Molecular Targets in Liver Disease

In the last decades, as the knowledge about the regulation of cellular processes has been growing, many new pharmacological targets have been emerging as promising tools for the management of liver disease. Protein kinases such as vascular endothelial growth factor receptor, platelet derived growth factor receptor, hepatocyte growth factor receptor and RAF kinases, are among the most researched pharmacological targets for the treatment of hepatocellular carcinoma and many small-molecule multiple kinase inhibitors are currently under development. Farnesoid X receptor, a nuclear receptor involved in the regulation of bile acid synthesis and transport has recently emerged as a pharmacological target for the treatment of primary cholangitis; its potential in non alcoholic fatty liver disease and non alcoholic steatohepatitis is also under evaluation in Phase III studies. Peroxisome proliferator-activated receptor α is a ligand-activated nuclear receptor enlisted among the main regulators of lipid metabolism in the liver, although it has other critical functions, including the regulation of canalicular transporters. Its ligands have been traditionally used as hypolipidemic agents; however, fibrates, a family of synthetic peroxisome proliferator-activated receptor agonists currently used in the treatment of primary cholangitis, are believed to work by modulating biliary secretion. Novel therapeutic targets are currently being studied and new drugs are under development. The Takeda G protein-coupled receptor 5 is involved in the progression of inflammatory processes in Kupffer cells and hepatic stellate cells. In cholangiocytes it promotes protective mechanisms against biliary toxicity; however, its overexpression promotes cholangiocyte proliferation potentially developing into cholangiocarcinoma. Immune checkpoint proteins are also interesting novel pharmacological targets. Programmed cell death protein 1 is expressed on the surface of hepatocellular carcinoma cells and promotes self-tolerance suppressing the activity of the immune system. Checkpoint inhibitors such as nivolumab have been introduced in the therapy of hepatocellular carcinoma even though they are currently under development, because of the promising results of Phase II studies.