Main Article Content
Abstract
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.
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References
- 1. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-89.
- 2. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216-33.
- 3. Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97(4):1235-94.
- 4. Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology. 2015;61(1):382-92.
- 5. Choi SS, Omenetti A, Diehl AM. The role of the Notch signaling pathway in biliary differentiation and function. Hepatobiliary Surg Nutr. 2013;2(4):247-56.
- 6. Apte U, Zeng G, Thompson MD, Micsenyi A, Cieply B, Bunton TE, et al. Wnt/β-catenin signaling in liver biology and pathobiology. Gene Expr. 2007;16(2):51-63.
- 7. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138(17):3593-612.
- 8. Yanger K, Zong Y, Maggs L, Shapira S, Madrigal B, Stanger BZ. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 2013;27(7):719-24.
- 9. Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2017;66(2):268-77.
- 10. Kwon YC, Sun PD. A new star in Notch therapy: targeting the Notch-ligand interaction. Cell Cycle. 2013;12(5):695-6.
- 11. Miele L. Notch signaling. Clin Cancer Res. 2006;12(4):1074-9.
- 12. Furukawa H, Nishioka Y, Tsuji T. Clinical and preclinical studies of gamma-secretase inhibitors: current status and future perspectives. Cancer Sci. 2020;111(3):927-35.
- 13. Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci. 2016;37(12):1081-96.
- 14. Ricklin D, Lambris JD. Therapies targeting the complement system. Nat Rev Nephrol. 2016;12(12):698-712.
- 15. Chen Y, Qiao S, Tano K, Ma L, Liang J. Notch signaling in liver disease. J Biomed Res. 2016;30(3):221-30.
- 16. Miyake Y, Yamasaki S, Sato K. Regulation of TGF-β signaling by Notch and BMP pathways in hepatic fibrosis. World J Hepatol. 2020;12(2):60-75.
- 17. Kao HF, Lee SM. Gamma-secretase inhibitor as a potential therapy for hepatic diseases: Mechanisms and clinical implications. Front Pharmacol. 2021;12:734920.
- 18. Zhang F, Hao F, An G. Notch signaling in liver malignancies: roles and therapeutic potentials. Front Oncol. 2021;11:714657.
- 19. Takebe T, Sekine K, Kimura M, et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Stem Cell. 2013;12(1):1-5.
- 20. Kitisin K, Saha T, Blake T, et al. TGF-β signaling in development. Sci STKE. 2007;2007(399):cm1.
- 21. Gridley T. Notch signaling in the vasculature. Curr Top Dev Biol. 2010;92:277-309.
- 22. Zalzali H, Nasr RG. Roles of the canonical and non-canonical forms of Notch in cancer. Biochimie. 2016;166:18-30.
- 23. Chinnadurai G. Approaches for the therapy of acute and chronic liver diseases by notch modulation. Clin Drug Investig. 2020;40(6):559-69.
- 24. Cordoba-Chacon J, Majumdar A, Suarez-Trujillo A. Interactions between Notch and metabolic pathways in the liver. Front Endocrinol. 2021;12:735175.
- 25. Manderfield LJ, High FA, Epstein JA. Notch in the heart: a complex journey from head to toe. Dev Biol. 2016;416(2):29-41.
- 26. Gil-Garcia Y, Baladrón V. The multifaceted role of Notch in liver disease. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165597.
- 27. Benedito R, Duarte A. Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. Gene Expr Patterns. 2005;5(6):750-5.
- 28. Weng AP, Ferrando AA. Notch signaling in leukemia. Curr Opin Hematol. 2016;20(4):254-60.
- 29. Tschaharganeh DF, Xue W, Calvisi DF, et al. p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell. 2014;158(1):579-92.
- 30. Zhao J, Shi W, Wang YF, Chen H, Cong W, Zhu H, et al. Role of Notch and Hedgehog signaling pathways in regulating liver progenitor cell proliferation and differentiation during rat acute liver failure repair. Biotechnol Lett. 2015;37(11):2405-15.
- 31. Real PJ, Ferrando AA. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia. 2009;23(8):1374-7.
- 32. Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010; 464 (7291):1052-7.
- 33. Meng RD, Shelton CC, Li Y, et al. Gamma-secretase inhibitors abrogate oxaliplatin-induced survival and augment drug sensitivity. Cancer Res. 2009;69(2):573-82
References
1. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-89.
2. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216-33.
3. Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97(4):1235-94.
4. Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology. 2015;61(1):382-92.
5. Choi SS, Omenetti A, Diehl AM. The role of the Notch signaling pathway in biliary differentiation and function. Hepatobiliary Surg Nutr. 2013;2(4):247-56.
6. Apte U, Zeng G, Thompson MD, Micsenyi A, Cieply B, Bunton TE, et al. Wnt/β-catenin signaling in liver biology and pathobiology. Gene Expr. 2007;16(2):51-63.
7. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138(17):3593-612.
8. Yanger K, Zong Y, Maggs L, Shapira S, Madrigal B, Stanger BZ. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 2013;27(7):719-24.
9. Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2017;66(2):268-77.
10. Kwon YC, Sun PD. A new star in Notch therapy: targeting the Notch-ligand interaction. Cell Cycle. 2013;12(5):695-6.
11. Miele L. Notch signaling. Clin Cancer Res. 2006;12(4):1074-9.
12. Furukawa H, Nishioka Y, Tsuji T. Clinical and preclinical studies of gamma-secretase inhibitors: current status and future perspectives. Cancer Sci. 2020;111(3):927-35.
13. Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci. 2016;37(12):1081-96.
14. Ricklin D, Lambris JD. Therapies targeting the complement system. Nat Rev Nephrol. 2016;12(12):698-712.
15. Chen Y, Qiao S, Tano K, Ma L, Liang J. Notch signaling in liver disease. J Biomed Res. 2016;30(3):221-30.
16. Miyake Y, Yamasaki S, Sato K. Regulation of TGF-β signaling by Notch and BMP pathways in hepatic fibrosis. World J Hepatol. 2020;12(2):60-75.
17. Kao HF, Lee SM. Gamma-secretase inhibitor as a potential therapy for hepatic diseases: Mechanisms and clinical implications. Front Pharmacol. 2021;12:734920.
18. Zhang F, Hao F, An G. Notch signaling in liver malignancies: roles and therapeutic potentials. Front Oncol. 2021;11:714657.
19. Takebe T, Sekine K, Kimura M, et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Stem Cell. 2013;12(1):1-5.
20. Kitisin K, Saha T, Blake T, et al. TGF-β signaling in development. Sci STKE. 2007;2007(399):cm1.
21. Gridley T. Notch signaling in the vasculature. Curr Top Dev Biol. 2010;92:277-309.
22. Zalzali H, Nasr RG. Roles of the canonical and non-canonical forms of Notch in cancer. Biochimie. 2016;166:18-30.
23. Chinnadurai G. Approaches for the therapy of acute and chronic liver diseases by notch modulation. Clin Drug Investig. 2020;40(6):559-69.
24. Cordoba-Chacon J, Majumdar A, Suarez-Trujillo A. Interactions between Notch and metabolic pathways in the liver. Front Endocrinol. 2021;12:735175.
25. Manderfield LJ, High FA, Epstein JA. Notch in the heart: a complex journey from head to toe. Dev Biol. 2016;416(2):29-41.
26. Gil-Garcia Y, Baladrón V. The multifaceted role of Notch in liver disease. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165597.
27. Benedito R, Duarte A. Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. Gene Expr Patterns. 2005;5(6):750-5.
28. Weng AP, Ferrando AA. Notch signaling in leukemia. Curr Opin Hematol. 2016;20(4):254-60.
29. Tschaharganeh DF, Xue W, Calvisi DF, et al. p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell. 2014;158(1):579-92.
30. Zhao J, Shi W, Wang YF, Chen H, Cong W, Zhu H, et al. Role of Notch and Hedgehog signaling pathways in regulating liver progenitor cell proliferation and differentiation during rat acute liver failure repair. Biotechnol Lett. 2015;37(11):2405-15.
31. Real PJ, Ferrando AA. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia. 2009;23(8):1374-7.
32. Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010; 464 (7291):1052-7.
33. Meng RD, Shelton CC, Li Y, et al. Gamma-secretase inhibitors abrogate oxaliplatin-induced survival and augment drug sensitivity. Cancer Res. 2009;69(2):573-82