R-Spondin Mimetic, SZN-043, Induced Proliferation and Expression of Wnt Target Genes, Two Impaired Features in Human Alcohol-Associated Liver Disease
Fisher, T.; Patel, M.; Deshmukh, S.; Shah, D.; Lu, C.; Newman, M.; Ye, J.; Fletcher, R.; Vanhove, G. F.; Tibbitts, J.; Li, Y.; Skill, N. J.; Yang, Z.; Liangpunsakul, S.; Baribault, H.
Show abstract
Liver regeneration is impaired in patients suffering from alcohol-associated liver (ALD) diseases. Wnt ligands and their FZD receptors are dysregulated in diseased livers. R-spondin and their receptors are known to regulate Wnt activity via the stabilization of FZD receptors. Here, we investigated the components of the Wnt and R-Spondin-signaling pathways and their activity in patients with ALD. We found that while hepatocytes retained high levels of differentiation markers such as ASGR1 and ASGR2, the expression of two R-spondin co-receptors, LGR4 and LGR5, and of Wnt target genes, CYP1A2 and others, were strongly reduced. SZN-043, a hepatocyte-targeted R-Spondin mimetic, is a new investigational drug that stimulates the physiological Wnt repair pathway and proliferation of hepatocytes. Here, we show that SZN-043 induced hepatocyte proliferation in all models tested, including humanized mouse livers, a chronic-binge alcohol-induced liver injury, and a CCl4-induced fibrosis mouse model. Altogether, SZN-043 could be beneficial for the treatment of ALD.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.