The role of roof plate-specific spondins in liver homeostasis and disease.

As evolutionarily conserved signals, roof plate-specific spondins (R-spondins; RSPOs) are a family with four members (RSPO1-4) exerting distinctly different functions. RSPOs have five receptors and correlate with different signaling pathways through these receptors and then perform various functions. Moreover, their best-known molecular function is the capacity to enhance WNT signaling pathways, which play critical roles in several processes. A recent study shows that RSPOs not only potentiate the WNT/beta (β)-catenin signaling pathway but are also involved in the WNT/planar cell polarity signaling pathway. RSPOs influence liver homeostasis and the development of multiple liver diseases. RSPO1 increases cell proliferation, protects hepatocytes from injury, improves liver regenerative potential, and affects liver metabolic zonation. RSPO2 not only regulates proliferation-associated genes and promotes differentiation in the liver but also participates in liver fibrosis through the WNT/β-catenin signaling pathway. RSPO3 is a key determinant of proper liver function, such as promoting hepatocyte regeneration and maintaining liver zonation. RSPO3 is upregulated in liver fibrosis and livers of patients with non-alcoholic steatohepatitis. Besides, RSPO2 and RSPO3 are confirmed as oncogenes and involved in the occurrence of liver cancer. The role of RSPO4 in the liver remains unclear. In this review, the structural and biochemical properties of RSPOs and their receptors and their roles in liver homeostasis and disease are summarized.