Background: Metabolic dysfunction–associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver-related mortality, yet no therapies directly target fibrosis in the later stages of the disease. Fibroblast growth factor 10 (FGF10) facilitates epithelial repair, yet its function and epithelial receptor requirements in chronic liver fibrogenesis are unclear.
Methods: We quantified hepatic FGF10 and fibroblast growth factor receptor 2 (FGFR2) expression across fibrosis stages in biopsies from patients with MASLD and mouse models. We then augmented hepatic FGF10 using adeno-associated virus-mediated liver expression or subcutaneous recombinant human FGF10 in carbon tetrachloride (CCl4) and high-fat diet plus CCl4-induced advanced fibrosis. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms.
Results: Hepatic FGF10 and FGFR2 protein expression were significantly reduced at advanced disease stages. Restoring FGF10 led to regression-associated remodelling of established bridging fibrosis, a decrease in inflammatory cytokines and a reduction in hepatocyte apoptosis, even with continued CCl4 exposure, indicating histologic regression rather than slowed progression. These therapeutic effects required hepatocyte FGFR2, as hepatocyte-specific FGFR2 deletion abolished protection and the associated transcriptional reprogramming of matrix and cytokine networks. In primary hepatocytes, FGF10 activated FGFR2–FGFR substrate 2α (FRS2α) signalling, increased inhibitory phosphorylation of glycogen synthase kinase 3β at Ser9 and suppressed nuclear factor kappa B, thereby lowering transforming growth factor β1 and other cytokines and indirectly limiting HSC activation. The efficacy extended to a high-fat diet plus CCl4 model of steatohepatitis.
Conclusions: These findings elucidate a hepatocyte-centric FGF10–FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte-targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression-associated architectural remodelling in advanced liver fibrosis.
Key points:
| [1] |
Stefan N, Yki-Järvinen H, Neuschwander-Tetri BA. Metabolic dysfunction-associated steatotic liver disease: heterogeneous pathomechanisms and effectiveness of metabolism-based treatment. Lancet Diabetes Endocrinol. 2025; 13(2): 134–148.
|
| [2] |
Wong VW, Ekstedt M, Wong GL, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol. 2023; 79(3): 842–852.
|
| [3] |
Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023; 77(4): 1335–1347.
|
| [4] |
Man S, Deng Y, Ma Y, et al. Prevalence of liver steatosis and fibrosis in the general population and various high-risk populations: a nationwide study with 5.7 million adults in China. Gastroenterology. 2023; 165(4): 1025–1040.
|
| [5] |
Ng CH, Lim WH, Hui Lim GE, et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023; 21(4): 931–939.e935.
|
| [6] |
Simon TG, Roelstraete B, Hagström H, Loomba R, Ludvigsson JF. Progression of non-alcoholic fatty liver disease and long-term outcomes: a nationwide paired liver biopsy cohort study. J Hepatol. 2023; 79(6): 1366–1373.
|
| [7] |
Schwabe RF, Tacke F, Sugimoto A, Friedman SL. Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease. JHEP Rep. 2025; 7(8):101421.
|
| [8] |
Steinberg GR, Carpentier AC, Wang D. MASH: the nexus of metabolism, inflammation, and fibrosis. J Clin Invest. 2025; 135(18):e186420.
|
| [9] |
Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024; 390(6): 497–509.
|
| [10] |
Taru V, Szabo G, Mehal W, Reiberger T. Inflammasomes in chronic liver disease: hepatic injury, fibrosis progression and systemic inflammation. J Hepatol. 2024; 81(5): 895–910.
|
| [11] |
Du C, Dong J, Wang Q, et al. Hastatoside attenuatescarbon tetrachloride-induced liver fibrosis by targeting glycogen synthase kinase-3β. Phytomedicine. 2023; 109:154585.
|
| [12] |
Wang C, Dong D, Zhao N, et al. Hepatocyte-specific C-C motif chemokine ligand 9 signaling promotes liver fibrosis progression in mice. Hepatology. 2025; 83(4): 789–807.
|
| [13] |
Gaul S, Leszczynska A, Alegre F, et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J Hepatol. 2021; 74(1): 156–167.
|
| [14] |
Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023; 20(10): 633–646.
|
| [15] |
Yang W, He H, Wang T, et al. Single-cell transcriptomic analysis reveals a hepatic stellate cell-activation roadmap and myofibroblast origin during liver fibrosis in mice. Hepatology. 2021; 74(5): 2774–2790.
|
| [16] |
Payen VL, Lavergne A, Alevra Sarika N, et al. Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep. 2021; 3(3):100278.
|
| [17] |
Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development—A molecular overview. Pharmacol Res. 2021; 170:105739.
|
| [18] |
Alvarez-Sola G, Uriarte I, Latasa MU, et al. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017; 66(10): 1818–1828.
|
| [19] |
Li X, Lu W, Kharitonenkov A, Luo Y. Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. J Intern Med. 2024; 295(3): 292–312.
|
| [20] |
Tan H, Yue T, Chen Z, Wu W, Xu S, Weng J. Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. Int J Biol Sci. 2023; 19(1): 66–88.
|
| [21] |
Berg T, Rountree CB, Lee L, et al. Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta-catenin activation. Hepatology. 2007; 46(4): 1187–1197.
|
| [22] |
Yang R, Liu S, Liang X, et al. TBBPA, TBBPS, and TCBPA disrupt hESC hepatic differentiation and promote the proliferation of differentiated cells partly via up-regulation of the FGF10 signaling pathway. J Hazard Mater. 2021; 401:123341.
|
| [23] |
Itoh N, Ohta H. Fgf10: a paracrine-signaling molecule in development, disease, and regenerative medicine. Curr Mol Med. 2014; 14(4): 504–509.
|
| [24] |
Zhou Q, Gong J, Bi J, et al. KGF-2 regulates STAP-2-mediated signal transducer and activator of transcription 3 signaling and reduces skin scar formation. J Invest Dermatol. 2022; 142(7): 2003–2013.e2005.
|
| [25] |
Yang X, Yang R, Chen M, et al. KGF-2 and FGF-21 poloxamer 407 hydrogel coordinates inflammation and proliferation homeostasis to enhance wound repair of scalded skin in diabetic rats. BMJ Open Diabetes Res Care. 2020; 8(1):e001009.
|
| [26] |
Chen J, Wang Z, Zheng Z, et al. Neuron and microglia/macrophage-derived FGF10 activate neuronal FGFR2/PI3K/Akt signaling and inhibit microglia/macrophages TLR4/NF-κB-dependent neuroinflammation to improve functional recovery after spinal cord injury. Cell Death Dis. 2017; 8(10):e3090.
|
| [27] |
Dong L, Li R, Li D, et al. FGF10 enhances peripheral nerve regeneration via the preactivation of the PI3K/Akt signaling-mediated antioxidant response. Front Pharmacol. 2019; 10: 1224.
|
| [28] |
Jeong BK, Choi WI, Choi W, et al. A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma. Nat Commun. 2024; 15(1): 6506.
|
| [29] |
Wang S, Li K, Pickholz E, Dobie R, et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023; 15(677):eadd3949.
|
| [30] |
Mederacke I, Dapito DH, Affò S, Uchinami H, Schwabe RF. High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat Protoc. 2015; 10(2): 305–315.
|
| [31] |
Li S, Zhu Z, Xue M, et al. The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice. Redox Biol. 2021; 40:101859.
|
| [32] |
Dong PD, Munson CA, Norton W, et al. Fgf10 regulates hepatopancreatic ductal system patterning and differentiation. Nat Genet. 2007; 39(3): 397–402.
|
| [33] |
Watson J, Ferguson HR, Brady RM, et al. Spatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival. Nat Commun. 2022; 13(1): 6589.
|
| [34] |
Lv YQ, Wu J, Li XK, Zhang JS, Bellusci S. Role of FGF10/FGFR2b signaling in mouse digestive tract development, repair and regeneration following injury. Front Cell Dev Biol. 2019; 7: 326.
|
| [35] |
Jung YS, Radhakrishnan K, Hammad S, et al. ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress. Redox Biol. 2024; 71:103107.
|
| [36] |
Chen JY, Yang YJ, Meng XY, et al. Oxysophoridine inhibits oxidative stress and inflammation in hepatic fibrosis via regulating Nrf2 and NF-κB pathways. Phytomedicine. 2024; 132:155585.
|
| [37] |
Lee J, Ha J, Kim JH, et al. Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3β phosphorylation and mitochondrial translocation. Exp Mol Med. 2023; 55(6): 1218–1231.
|
| [38] |
Zhang QH, Jin LM, Lin MS, et al. FNDC5/irisin exacerbates APAP-induced acute liver injury through activating JNK/NF-κB and inflammatory response. Acta Pharmacol Sin. 2025; 46(7): 1946–1957.
|
| [39] |
Dai C, Yusuf A, Sun H, Shu G, Deng X. A characterized saponin extract of Panax japonicus suppresses hepatocyte EMT and HSC activation in vitro and CCl(4)-provoked liver fibrosis in mice: roles of its modulatory effects on the Akt/GSK3β/Nrf2 cascade. Phytomedicine. 2021; 93:153746.
|
| [40] |
Mao H, Zhao X, Sun SC. NF-κB in inflammation and cancer. Cell Mol Immunol. 2025; 22(8): 811–839.
|
| [41] |
Beuers U, Banales JM, Karpen SJ, Keitel V, Williamson C, Trauner M. The history and future of bile acid therapies. J Hepatol. 2025; 83(5): 1172–1188.
|
| [42] |
Rose JP, Morgan DA, Sullivan AI, et al. FGF21 reverses MASH through coordinated actions on the CNS and liver. Cell Metab. 2025; 37(7): 1515–1529.e1516.
|
| [43] |
Xu H, Fang F, Wu K, et al. Gut microbiota-bile acid crosstalk regulates murine lipid metabolism via the intestinal FXR-FGF19 axis in diet-induced humanized dyslipidemia. Microbiome. 2023; 11(1): 262.
|
| [44] |
Mauduit O, Aure MH, Delcroix V, et al. A mesenchymal to epithelial switch in Fgf10 expression specifies an evolutionary-conserved population of ionocytes in salivary glands. Cell Rep. 2022; 39(2):110663.
|
| [45] |
Rice R, Spencer-Dene B, Connor EC, et al. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest. 2004; 113(12): 1692–1700.
|
| [46] |
Lu X, Chen H, Patterson AV, Smaill JB, Ding K. Fibroblast growth factor receptor 4 (FGFR4) selective inhibitors as hepatocellular carcinoma therapy: advances and prospects. J Med Chem. 2019; 62(6): 2905–2915.
|
| [47] |
Feng G, Valenti L, Wong VW, et al. Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2024; 21(1): 46–56.
|
| [48] |
AlWahsh M, Othman A, Hamadneh L, et al. Second exposure to acetaminophen overdose is associated with liver fibrosis in mice. Excli J. 2019; 18: 51–62.
|
| [49] |
Hammad S, Ogris C, Othman A, et al. Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation. Cell Death Dis. 2023; 14(7): 414.
|
| [50] |
Yan M, Cui Y, Xiang Q. Metabolism of hepatic stellate cells in chronic liver diseases: emerging molecular and therapeutic interventions. Theranostics. 2025; 15(5): 1715–1740.
|
| [51] |
Guilliams M, Bonnardel J, Haest B, et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022; 185(2): 379–396.e338.
|
| [52] |
Tao L, Yang G, Sun T, et al. Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1. J Hepatol. 2023; 78(4): 805–819.
|
| [53] |
Filliol A, Saito Y, Nair A, et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature. 2022; 610(7931): 356–365.
|
| [54] |
Martínez García de la Torre RA, Vallverdú J, Xu Z, et al. Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis. Nat Commun. 2025; 16(1): 1489.
|
| [55] |
Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab. 2024; 36(7): 1439–1455.
|
| [56] |
Kaffe E, Roulis M, Zhao J, et al. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell. 2023; 186(18): 3793–3809.e3726.
|
| [57] |
Hashimoto T, Iida N, Kadowaki S, et al. FGFR2-IIIc isoform detection reveals prognostic prevalence and a functional link to mesenchymal transition in gastric and gastroesophageal junction cancer. ESMO Open. 2025; 10(11):105851.
|
| [58] |
Smyth EC, Kim KM, Rha SY, et al. FGFR2b protein overexpression: an emerging biomarker in gastric and gastroesophageal junction adenocarcinoma. Cancer Treat Rev. 2025; 139:102971.
|
| [59] |
Vogel A, Segatto O, Stenzinger A, Saborowski A. FGFR2 inhibition in cholangiocarcinoma. Annu Rev Med. 2023; 74: 293–306.
|
RIGHTS & PERMISSIONS
2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PDF
(13646KB)
