Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver

Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a rangeof cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrantactivation has been associated with the development of hepatic tumours. Despite great advances in earlydiagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate,owing primarily to high molecular heterogeneity and unclear molecular targeting. The development ofFGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 andseveral clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma(HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHObrepresents a novel therapeuticstrategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, whichcould potentially prevent the development of metabolic HCC. Herein, we provide an overview of thecurrently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlightingthe need to carefully stratify patients and personalise therapeutic strategies. (c) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Automated summary

FGFR4 and its ligand FGF19 play crucial roles in cellular processes, including the development of liver tumors. FGFR4 inhibitors are a promising treatment option for HCC, while using FGF19 analogues to activate FGFR4-KLOTHO represents a novel therapeutic strategy for other liver diseases.