Notch Signalling in Liver Disease: A Comprehensive Analysis

Notch signaling is an evolutionarily conserved cell–cell communication pathway that exerts broad regulatory functions across numerous developmental and pathophysiological contexts. In the liver, Notch signaling intricately controls hepatobiliary differentiation, biliary homeostasis, and regenerative processes. Dysregulated Notch activity underlies the pathogenesis of diverse liver diseases, including cholangiopathies, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). This manuscript provides a comprehensive overview of Notch biology in the liver, highlighting molecular mechanisms of pathway activation, cross-talk with other signaling cascades, and the resultant outcomes in both normal physiology and disease states. Emphasis is placed on recent advances that delineate how aberrant Notch signaling contributes to cholangiocyte proliferation, fibrogenesis, hepatic steatosis, and tumorigenesis. Furthermore, current therapeutic strategies targeting Notch—ranging from γ-secretase inhibitors and monoclonal antibodies to ligand-specific traps and novel gene-based approaches—are discussed in light of their potential benefits and limitations. Emerging evidence suggests that targeted modulation of Notch may offer new possibilities for disease management, either alone or in combination with other targeted therapies. Nonetheless, toxicity and off-target effects pose ongoing challenges, underscoring the need for refined, context-specific interventions. By examining the molecular underpinnings and clinical implications of Notch signaling in liver diseases, this review aims to inform future research directions and therapeutic developments. The ultimate objective is to propel the field toward precision medicine strategies that more effectively leverage Notch pathway modulation for improved patient outcomes in diverse hepatic disorders.