Reframing Wnt/β-Catenin Signalling in Liver Fibrosis: Transcriptional State Regulation by CBP and p300.

Liver fibrosis is a shared pathological phenotype of chronic liver diseases of diverse etiologies, including viral hepatitis, alcohol-associated liver disease and metabolic dysfunction-associated steatohepatitis (MASH), as well as cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis, and may progress to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Despite advances in etiological treatments, effective therapies for established fibrosis remain limited. Increasing evidence indicates that liver fibrosis is a dynamic and potentially reversible process. The Wnt/β-catenin pathway is central to both liver regeneration and fibrogenesis and has traditionally been interpreted in terms of quantitative activation. Recent studies demonstrate that β-catenin-dependent transcription is qualitatively regulated by its nuclear coactivators, CREB-binding protein (CBP) and p300. CBP- and p300-associated transcriptional programmes exert distinct biological effects, promoting fibrogenic or regenerative states, respectively. These findings support a broader conceptual framework in which liver fibrosis can be viewed as a transcriptionally regulated and potentially reversible pathological state. In this review, we first summarize the molecular basis of canonical Wnt/β-catenin signalling and its transcriptional regulation by CBP and p300. Then, we discuss the pathophysiological relevance of CBP- versus p300-dependent β-catenin transcription in liver fibrosis of various etiologies, including cholestatic injury, and review experimental and early clinical evidence suggesting that selective modulation of CBP-associated transcription may promote early functional recovery, potentially preceding measurable regression of fibrotic burden. We close by considering implications for clinical trial design and the importance of function-oriented endpoints in antifibrotic drug development.