The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration and disease

WNT/β-catenin signaling plays pivotal roles during liver development, homeostasis and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for the society and a hallmark of non-alcoholic-steatohepatitis (NASH), can also be promoted by WNT/β-catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/β-catenin activity may constitute targets for the development of novel therapies addressing these life-threatening conditions. The RSPO-LGR4/5-ZNRF3/RNF43 module is fine-tuning WNT/β-catenin signaling in several tissues and is essential for hepatic WNT/β-catenin activity. In this review article, we recapitulate the role of the RSPO-LGR4/5-ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration and disease. We further discuss the controversy around LGR5 as a liver stem cell marker.