The incidence of liver disease continues to rise, and liver fibrosis, as the early stage of cirrhosis and liver cancer, has attracted much attention. Hedgehog (Hh) signaling pathway plays a key role in the progression of liver fibrosis. In the process of liver fibrosis, Hh signaling pathway is involved in several key pathological links. It can regulate the activation, proliferation and apoptosis of hepatic stellate cells (HSC), affect the remodeling of hepatic blood vessels, regulate the function of inflammatory cells and inflammatory response, promote the proliferation of hepatic progenitor cells and epithelial-mesenchymal transdifferentiation (EMT). Many studies have shown that Hh signaling pathway is a potential therapeutic target for liver fibrosis, and related inhibitors have been shown to be effective in animal and cell experiments, but the precise mechanism of this pathway in liver fibrosis is still not fully understood, and the results of clinical trials are not clear. In the future, in-depth exploration of the role of Hh signaling pathway in the occurrence and development of liver fibrosis and the injury mechanism to achieve safe and effective regulation of it is of great significance to optimize liver regeneration and prevent liver fibrosis deterioration, and is expected to provide a reliable basis for the clinical treatment of liver fibrosis.

Keyu Shao, Lanzhen Xu. Hedgehog signaling pathway as a potential therapeutic target for liver fibrosis. International Journal of Frontiers in Medicine (2025), Vol. 7, Issue 1: 50-55. https://doi.org/10.25236/IJFM.2025.070108.

[1] Xiao J, Wang F, Yuan Y, et al. Epidemiology of liver diseases: global disease burden and forecasted research trends[J]. Sci China Life Sci,2024.

[2] Gong L, Wei F, Gonzalez F J, et al. Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines[J]. Hepatology,2023,78(5):1625-1653.

[3] Yasukawa K, Shimizu A, Kubota K, et al. Impact of Liver Fibrosis Severity on Oncological Prognosis in Hepatocellular Carcinoma[J]. Liver Cancer,2024,13(2):150-160.

[4] Somnay K, Wadgaonkar P, Sridhar N, et al. Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives[J]. Biomedicines,2024,12(10).

[5] Zhang F, Hao M, Jin H, et al. Canonical hedgehog signalling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis[J]. Br J Pharmacol,2017,174(5):409-423.

[6] Hu Y, Bao X, Zhang Z, et al. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling[J]. Theranostics,2024,14(6):2379-2395.

[7] Nellas I, Iyer K V, Iglesias-Artola J M, et al. Hedgehog signaling can enhance glycolytic ATP production in the Drosophila wing disc[J]. EMBO Rep,2022,23(11):e54025.

[8] Kaushal J B, Batra S K, Rachagani S. Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review[J]. Cell Mol Life Sci,2022,79(5):266.

[9] Rowton M, Perez-Cervantes C, Hur S, et al. Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages[J]. Dev Cell, 2022,57(18):2181-2203.

[10] Jiayuan S, Junyan Y, Xiangzhen W, et al. Gant61 ameliorates CCl(4)-induced liver fibrosis by inhibition of Hedgehog signaling activity[J]. Toxicol Appl Pharmacol,2020,387:114853.

[11] Mosoh D A. Widely-targeted in silico and in vitro evaluation of veratrum alkaloid analogs as FAK inhibitors and dual targeting of FAK and Hh/SMO pathways for cancer therapy: A critical analysis[J]. Int J Biol Macromol,2024,281(Pt 2):136201.

[12] Roy L, Roy A, Bose D, et al. Unraveling the structural aspects of the G-quadruplex in SMO promoter and elucidating its contribution in transcriptional regulation[J]. J Biomol Struct Dyn, 2024,42(22):12228-12243. 

[13] Sanna M D, Ghelardini C, Galeotti N. Differential contribution of Galphai/o subunits in the response to food deprivation[J]. Eur J Pharmacol,2015,750:27-31.

[14] An R, Wilms E, Masclee A A M, et al. Age-dependent changes in GI physiology and microbiota: time to reconsider?[J]. Gut,2018,67(12):2213-2222.

[15] Zhang Q, Jiang J. Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination[J]. Int J Mol Sci,2021,22(24).

[16] Ng S S, Saeb-Parsy K, Blackford S J I, et al. Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold[J]. Biomaterials, 2018, 182:299-311.

[17] Shaheen R, Alsahli S, Ewida N, et al. Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans[J]. Hepatology, 2020, 71(6):2067-2079.

[18] Kumar V, Kumar V, Luo J, et al. Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis[J]. Mol Ther,2018,26(12):2798-2811.

[19] Marbach-Breitruck E, Matz-Soja M, Abraham U, et al. Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis[J]. J Hepatol,2019,70(6):1192-1202.

[20] Shen X, Peng Y, Li H. The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis[J]. Front Immunol,2017,8:1450.

[21] Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A  molecular overview[J]. Pharmacol Res,2021,170:105739.

[22] Wu Y, Ding Z, Jin G, et al. Autocrine transforming growth factor-beta/activin A-Smad signaling induces hepatic progenitor cells undergoing partial epithelial-mesenchymal transition states[J]. Biochimie,2018,148:87-98.

[23] Zhangdi H, Su S, Wang F, et al. Crosstalk network among multiple inflammatory mediators in liver fibrosis[J]. World J Gastroenterol,2019,25(33):4835-4849.

[24] Yan J, Hu B, Shi W, et al. Gli2-regulated activation of hepatic stellate cells and liver fibrosis by TGF-beta signaling[J]. Am J Physiol Gastrointest Liver Physiol,2021,320(5):G720-G728.

[25] Gao W, Sun J, Wang F, et al. Deoxyelephantopin suppresses hepatic stellate cells activation associated with inhibition of aerobic glycolysis via hedgehog pathway[J]. Biochem Biophys Res Commun,2019,516(4):1222-1228.

[26] Chen L, Gu T, Li B, et al. Delta-like ligand 4/DLL4 regulates the capillarization of liver sinusoidal endothelial cell and liver fibrogenesis[J]. Biochim Biophys Acta Mol Cell Res, 2019, 1866(10):1663-1675.

[27] Lafoz E, Ruart M, Anton A, et al. The Endothelium as a Driver of Liver Fibrosis and Regeneration [J]. Cells,2020,9(4).

[28] de Haan W, Dheedene W, Apelt K, et al. Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis[J]. Cardiovasc Res,2022,118(5):1262-1275.

[29] Yang L, Yue W, Zhang H, et al. Dual Targeting of Angipoietin-1 and von Willebrand Factor by microRNA-671-5p Attenuates Liver Angiogenesis and Fibrosis[J]. Hepatol Commun, 2022, 6(6):1425-1442.

[30] Hinshaw D C, Hanna A, Lama-Sherpa T, et al. Hedgehog Signaling Regulates Metabolism and Polarization of Mammary Tumor-Associated Macrophages[J]. Cancer Res,2021,81(21):5425-5437.

[31] Ustiuzhanina M O, Streltsova M A, Timofeev N D, et al. Autologous T-Cell-Free Antigen Presentation System Unveils hCMV-Specific NK Cell Response[J]. Cells,2024,13(6).

[32] Heinrichs D, Brandt E F, Fischer P, et al. Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations[J]. Cells,2021,10(2).

[33] Overi D, Carpino G, Cardinale V, et al. Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases[J]. Int J Mol Sci,2018,19(10).

[34] Byerly C D, Mitra S, Patterson L L, et al. Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program[J]. PLoS Pathog,2022,18(5):e1010345.

[35] Li B, Li F, Gu T, et al. Specific knockdown of Y-box binding protein 1 in hepatic progenitor cells inhibits proliferation and alleviates liver fibrosis[J]. Eur J Pharmacol,2022,921:174866.

[36] Cao Y. Lack of basic rationale in epithelial-mesenchymal transition and its related concepts[J]. Cell Biosci, 2024,14(1):104.

[37] Solhi R, Lotfi A S, Lotfinia M, et al. Hepatic stellate cell activation by TGFbeta induces hedgehog signaling and endoplasmic reticulum stress simultaneously[J]. Toxicol In Vitro,2022,80:105315.

[38] Wu H, Chen C, Ziani S, et al. Fibrotic Events in the Progression of Cholestatic Liver Disease[J]. Cells, 2021,10(5).