Notch signaling in liver diseases: mechanistic insights and therapeutic implications

The Notch signaling pathway represents an evolutionarily conserved mechanism of intercellular communication that plays critical roles in organ development and tissue homeostasis. However, its functions in liver physiology and pathology demonstrate remarkable context-dependent characteristics, with dysregulated signaling contributing to various liver disorders. This review systematically summarizes the complex roles of Notch signaling in liver health and disease. It comprehensively examines the pathway's essential functions in biliary development, hepatic regeneration, and metabolic homeostasis, while providing a detailed analysis of its pathogenic mechanisms in conditions including Alagille syndrome, drug-induced liver injury, non-alcoholic fatty liver disease, liver fibrosis, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma. Our review particularly emphasizes the dual function of Notch signaling in hepatobiliary malignancies, where it can exert either oncogenic or tumor-suppressive effects depending on specific cellular contexts, molecular interactions, and microenvironmental cues. Furthermore, we highlight the evolution of therapeutic strategies from broad-spectrum γ-secretase inhibitors to more precise approaches involving ligand-specific antibodies, transcriptional complex blockers, and pathway agonists, while addressing persistent challenges in clinical translation including on-target toxicities, compensatory resistance mechanisms, and context-dependent responses. Looking forward, this review outlines promising research directions featuring biomarker-guided patient stratification, rational combination therapies with immune checkpoint inhibitors, and spatiotemporally precise regulatory strategies. By integrating foundational knowledge with recent advances, this work provides valuable insights for understanding Notch signaling's complex roles in liver pathophysiology and for developing novel therapeutic interventions.