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 society and a hallmark of 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 R‐spondin (RSPO)–leucine‐rich repeat‐containing G protein‐coupled receptor (LGR) 4/5–zinc and ring finger (ZNRF) 3/ring finger 43 (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.