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bioRxiv · 10.1101/2024.11.19.624277

R-Spondin Mimetic, SZN-043, Induced Proliferation and Wnt Activity, Two Features Deficient 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.
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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.

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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.. 2024-11-22. R-Spondin Mimetic, SZN-043, Induced Proliferation and Wnt Activity, Two Features Deficient in Human Alcohol-Associated Liver Disease. https://doi.org/10.1101/2024.11.19.624277

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