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

WNT/beta-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/beta-catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/beta-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/beta-catenin signaling in several tissues and is essential for hepatic WNT/beta-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.

Automated summary

WNT/β-catenin signaling is key in liver development, homeostasis, and regeneration, but its dysregulation can lead to hepatic tumors. The RSPO-LGR4/5-ZNRF3/RNF43 module fine-tunes WNT/β-catenin signaling and may offer targets for novel therapies. Controversy surrounds LGR5 as a marker for liver stem cells.