Targeting ZNRF3 and RNF43 to Restore Regeneration and Reverse Metabolic Dysfunction-Associated Steatotic Liver Disease

Liver regeneration and hepatocyte metabolic identity are disrupted in metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms of restore liver regeneration and reprogram metabolism for disease reversal remains poorly understood. Here, we show that β-Catenin activity progressively declines in hepatocytes during MASH in both humans and mice, coinciding with impaired regeneration and defective lipid clearance. Targeted deletion of the endogenous WNT pathway inhibitors ZNRF3 and RNF43 in hepatocytes after MASH onset reactivates β-Catenin signaling, leading to robust regression of steatosis, inflammation, and fibrosis, and restoring regenerative capacity across multiple fatty liver disease models. Mechanistically, this therapeutic effect is driven by β-Catenin–dependent induction of the alternative bile acid synthesis pathway without disrupting systemic lipid homeostasis. Importantly, both short-and long-term deletion of ZNRF3/RNF43 restores liver function without triggering tumorigenesis or hepatotoxicity, indicating a safe therapeutic window. These findings reveal that physiological activation of WNT/β-catenin signaling via ZNRF3 and RNF43 offers a viable regenerative and metabolic strategy for reversing fatty liver disease.