ArticleGastro hep advances2026
A Targeted R-Spondin Mimetic Induces Hepatocyte-Specific Activation of Wnt Signaling and Cell Proliferation in Mice.
Article in Gastro hep advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background and Aims: Injection of an antibody-based WNT mimetic or R-spondin (RSPO) protein in mice has been reported to activate Wnt signaling in the liver. Furthermore, a therapeutic hepatocyte-targeted RSPO mimetic antibody, SZN-043, has entered a multiple ascending dose phase 1b trial in patients with severe alcoholic hepatitis. To address key questions regarding therapeutic Wnt signaling agonism and RSPO-based therapy, impacts of different Wnt-activating treatments to the liver gene expression landscape and metabolic zonation were investigated. Methods: Naive mice were treated with a WNT mimetic, RSPO2, or in combination to assess their impacts on metabolic zonation in the liver. To address its hepatocyte specificity, the effects of SZN-043 on liver cell transcriptome were investigated using single-cell RNA sequencing in a 14-day daily injection study followed with washout periods. Its effect on hepatocyte proliferation was investigated in a subsequent study using Edu labeling to track cell proliferation. Results: SZN-043 injection, compared with Wnt/β-catenin signaling activation through co-injection of a WNT mimetic and RSPO2, induced strong pathway activation specifically in hepatocytes. Sustained SZN-043 treatment led to bona fide zonal metabolic gene expression profile changes. However, unlike the effects from Wnt pathway-activating mutations, the agonist-based treatment effects are quickly reversed after treatment cessation. SZN-043 also induced robust hepatocyte proliferation that was transient and zone-biased. We also identified and assessed several serum pharmacodynamic biomarker candidates in a preclinical setting. Conclusion: This work provides insights into Wnt signaling agonism applications for liver regeneration, particularly the mechanism and dynamics of SZN-043 activity, thus supporting its further clinical investigation.
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