Wnt信号通路调控代谢相关脂肪性肝病肝纤维化的机制及临床应用前景

Mechanism of the Wnt signaling pathway regulating hepatic fibrosis associated with metabolic dysfunction-associated fatty liver disease and its application prospects

摘要

代谢相关脂肪性肝病（MAFLD）目前已成为世界范围内需重点关注的慢性肝病之一，MAFLD患者的肝纤维化程度与其预后紧密相关，因此控制甚至逆转肝纤维化是MAFLD患者长期管理中不可忽视的部分。大量研究表明，Wnt信号通路参与MAFLD的发生发展过程。本文系统描述了Wnt信号通路，并重点阐述Wnt信号通路在MAFLD相关肝纤维化中的作用机制，为MAFLD患者肝纤维化的治疗提供参考。

Abstract

Metabolic dysfunction-associated fatty liver disease （MAFLD） has become one of the critical chronic liver diseases requiring global attention， and the degree of hepatic fibrosis in these patients is closely associated with their prognosis. Therefore， control or even reversal of hepatic fibrosis is an indispensable part of the long-term management of MAFLD patients. A large number of studies have shown that the Wnt signaling pathway is involved in the development and progression of MAFLD. This article systematically describes the Wnt signaling pathway and elaborates on its mechanism of action in MAFLD-associated hepatic fibrosis， in order to provide a reference for the treatment of hepatic fibrosis in patients with MAFLD.

Graphical abstract

关键词

代谢相关脂肪性肝病 / Wnt信号通路 / 肝纤维化

Key words

Metabolic Dysfunction-Associated Fatty Liver Disease / Wnt Signaling Pathway / Hepatic Fibrosis

脂肪肝是指肝细胞脂肪变性比例超过正常肝组织的5%，通常认为该病变与过量饮酒相关，因此使用非酒精性脂肪性肝病（NAFLD）描述少量或不饮酒造成的脂肪肝。随着研究深入，国际专家共识建议使用代谢相关脂肪性肝病（metabolic dysfunction-associated fatty liver disease，MAFLD）和代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）代替NAFLD^［1-3］，本文依据《代谢相关（非酒精性）脂肪性肝病防治指南（2024年版）》^［4］，仍使用MAFLD这一名称。MAFLD病程涵盖单纯肝脂肪变性、代谢相关脂肪性肝炎（metabolic dysfunction-associated steatohepatitis，MASH）、肝纤维化、肝硬化及晚期肝癌^［5］。随着对HBV与HCV感染的积极预防与治疗，HBV与HCV所致的肝纤维化、肝硬化和肝癌发病率呈下降趋势，但MAFLD肝纤维化发病率逐渐增加，成为严峻的公共卫生问题^［6-7］，其严重程度与患者的死亡及预后密切相关^［8］。

Wnt信号通路是调控细胞增殖、分化的重要机制之一，也参与MAFLD的疾病进展^［9］。本文重点综述Wnt信号通路在MAFLD肝纤维化中的作用，以期为MAFLD患者肝纤维化的治疗提供新思路。

１ Wnt信号通路概述

依赖β-catenin蛋白的经典信号通路、Wnt/平面细胞极性通路（Wnt/PCP）与Wnt/Ca²⁺信号通路是三大主要的Wnt信号通路（图1）。Wnt信号通路在成熟健康的肝脏中基本处于失活状态，而在再生或病理状态下会被重新激活^［10］。经典通路由Wnt蛋白配体（如Wnt2、Wnt3a等）、卷曲蛋白（frizzled，Fzd）与低密度脂蛋白受体相关蛋白5/6（low-denslty lipoprotein receptor related protein 5/6，LRP-5/6）组成的受体复合物、细胞质散乱蛋白（dishevelled，Dvl）、结直肠腺瘤性息肉基因病蛋白（adenomatous polyposis coli，APC）、酪蛋白激酶1（casein kinase 1，CK1）、糖原合成酶激酶3β（glycogen synthase kinase 3β，GSK-3β）、轴蛋白（Axin）及β-catenin蛋白等组成。激活时，Wnt配体与受体Fzd和LRP-5/6结合，激活Dvl，使β-catenin与降解复合物（Axin/APC/CK1/GSK-3β）解离；胞质内的β-catenin单体逐渐积累进入细胞核，与核内T细胞因子/淋巴细胞增强因子（T cell factor/lymphoid enhancer factor，TCF/LEF）结合，形成TCF/LEF/β-catenin复合物，进而启动靶基因的转录^［11-12］。非经典Wnt通路分为两个分支：Wnt/PCP通过配体（如Wnt5a）与Fzd受体、酪氨酸激酶样孤儿受体2（receptor tyrosine kinase-like orphan receptor 2，ROR2）或酪氨酸激酶样受体（receptor tyrosine kinase-like，Ryk）结合，触发RhoA/JNK信号，调控细胞极性与迁移^［12］。Wnt/Ca²⁺信号通路则通过G蛋白和磷脂酶C增加胞内Ca²⁺浓度，激活蛋白激酶C（protein kinase C，PKC）、钙/钙调蛋白依赖性蛋白激酶Ⅱ（calcium/calmodulin-dependent protein kinase Ⅱ，CaMK-Ⅱ）、活化T细胞核因子（nuclear factor of activated T-cells，NFAT）通路，调控细胞黏附和运动^［12］。此外，CaMK-Ⅱ还可通过转化生长因子β活化激酶1（transforming growth factor-β-activated kinase 1，TAK1）和Nemo样激酶（Nemo-like kinase，NLK），使TCF发生磷酸化，使其失去与β-catenin结合的能力，从而负向调控经典通路^［13］。

2 Wnt信号通路与MAFLD肝纤维化

2.1 MAFLD肝纤维化的主要机制

肝纤维化本质是肝脏慢性损伤后的异常修复反应，其核心机制涉及多因素驱动的肝细胞损伤、HSC活化及ECM异常沉积。在肝脏中，HSC转化为肌成纤维细胞，是分泌ECM的主要细胞，也是多种病因导致纤维化的关键环节。在MAFLD背景下，脂肪组织功能异常、胰岛素抵抗、脂毒性与遗传因素共同作用，引发肝细胞脂质沉积、线粒体功能障碍及内质网应激，导致肝细胞损伤、氧化应激和慢性炎症。原本处于静止状态的HSC，在受损肝细胞、炎性细胞、ROS和促炎因子构成的促纤维化微环境中被直接或间接激活^［14-15］。同时，MMP和TIMP之间的平衡被打破，导致ECM过度沉积和结构重塑。此外，肠道菌群紊乱、有害代谢产物增多，以及肠道屏障损伤均可能进一步加剧炎症反应和加快肝纤维化进程^［16］。

2.2 Wnt信号通路参与肝纤维化

肝纤维化的多个环节中，Wnt信号发挥着复杂的调控作用。Wnt1、Wnt3a、Wnt5a、Wnt10a、Wnt10b等信号表达上调，与HSC的活化和增殖相关，并抑制其凋亡，促进ECM沉积^［17-20］。Xi等^［21］报道，Wnt1可与TNF-α、TGF-β等协同作用，诱导下游的Wnt1信号通路蛋白1表达，增强HSC的迁移能力。此外，Wnt1在肾纤维化中能诱导线粒体功能障碍及氧化应激的产生，提示肝脏中也可能存在类似机制^［22］。经典Wnt通路的关键激活剂Wnt3a，可使HSC发生糖酵解代谢重编程^［18］，还能抑制PPAR-α和PPAR-γ亚型，促进HSC激活和转化，加剧肝纤维化发展^［23-24］。Wnt5b激活非经典Wnt通路，诱导肝祖细胞向肌成纤维细胞转分化^［19］，并可能与TGF-β协同增强HSC活化^［25］。Wnt10b也可能通过抑制PPAR-γ，影响HSC脂质代谢，维持其活化表型^［20］。

部分Wnt分子发挥双向调控作用。Wnt3a虽主要发挥促肝纤维化效应，但也可促进肝祖细胞增殖和迁移、改善肠道血管内皮屏障，具有潜在缓解肝纤维化的作用^［26-27］。活化的HSC中Wnt2呈高表达，与肝纤维化相关^［9］，但也能协同肝细胞生长因子，促进肝再生^［28］。Chen等^［29］实验发现，LSEC旁分泌的Wnt2能够促进肝细胞增殖。Wnt2也维持LSEC的分化状态，其下调会促进LSEC毛细血管化，促使HSC活化^［30］。Wnt2b能促进HSC的活化和ECM的沉积^［31］，也能抑制Toll样受体4（TLR4），减弱HSC对TGF-β的敏感性，表现出相反作用^［32］。此外，Wnt3可促进肝细胞再生，抑制肝纤维化进展^［33］。但肠上皮细胞中Wnt3上调可能破坏上皮细胞稳定，通过肠肝轴促进肝纤维化^［34］。Wnt5a、Wnt5b能促进肝纤维化进展，也能促进肝祖细胞增殖和胆管反应细胞分化，有助于肝脏修复^{［19，26］}，但胆管反应细胞对肝脏再生的贡献有限，甚至可能导致肝纤维化^［35］。部分Wnt亚型还可能发挥单一抗肝纤维化作用。Wnt9b与Wnt2缓解肝纤维化机制类似，能维持LSEC分化状态，抑制HSC活化^［30］。肾纤维化中Wnt6表现出的抗纤维化特性，为肝纤维化研究提供新思路，其作用仍需进一步探讨^［36］。另外，Wnt7a、Wnt8b、Wnt16等在其他器官的纤维化中被报道，但在肝纤维化中的功能尚未明确（表1）。

2.3 Wnt信号通路调节MAFLD肝纤维化

在病毒性、酒精性或药物性肝损伤中，直接的肝细胞毒性损伤、强烈的炎症反应及特定病原体/毒素的直接作用，共同激活Wnt通路参与肝纤维化进展^［37-38］。而在MAFLD中，特有的代谢紊乱与Wnt信号的相互作用，共同驱动HSC活化和ECM过度沉积。Wnt/β-catenin通路的激活可通过调节内质网应激，导致肝细胞胰岛素抵抗和脂肪生成，从而促进MASH^［39］。Wnt通路的下游核转录因子TCF7L2与脂质代谢、葡萄糖稳态相关，也能够通过β-catenin/TCF通路调节肝脏中HSC的激活和纤维化^［40］。Wnt3a激活经典通路，上调糖酵解关键酶（如乳酸脱氢酶A），重塑HSC的糖酵解代谢，支持纤维化进展^［18］。PPAR家族参与在MAFLD的发病机制中，被证实在调节胰岛素抵抗、脂质代谢、肥胖和炎症方面发挥重要作用^［41］。Wnt家族与PPAR相互抑制，抑制脂肪细胞分化，促进HSC激活，导致肝纤维化进展^［23-24］。此外，一种特殊的Wnt配体——主动脉羧肽酶样蛋白，也能激活HSC中的经典Wnt通路，减弱PPAR-γ信号，促进HSC活化并加剧MASH中肝纤维化的进展^［42］。

3 调节Wnt信号通路对MAFLD肝纤维化的治疗作用

治疗MAFLD目前仍以减重和调节生活方式为核心，甲状腺激素受体β激动剂Resmetirom是首个被批准用于治疗MASH肝纤维化的药物^［43］。其他药物如PPAR激动剂、法尼酯X受体激动剂和胰高血糖素样肽-1受体（glucagon-like peptide-1 receptor，GLP-1）激动剂等正处于临床试验阶段。多元化的Wnt信号通路抑制剂在抗肝纤维化领域被广泛研究^［9］，尽管针对MAFLD纤维化的研究尚处于早期阶段，但Wnt信号通路的复杂性和多样性为药物开发提供了丰富的潜在靶点。

3.1 Wnt信号通路调节剂影响MAFLD肝纤维化

Wnt信号通路调节剂不仅调节信号通路成分及其调节因子，还可与其他代谢、炎症相关通路相互串扰以发挥作用。恩波吡维铵作为Wnt通路抑制剂，能显著下调Fzd7和Wnt3a表达，同时上调Wnt2和Fzd5，在MASH模型中减轻肝脂肪变性及胶原沉积，且可抑制Hedgehog通路^［44］。PPAR-α激动剂油酰乙醇酰胺能够抑制Wnt3a/β-catenin信号通路，减少炎症反应和氧化应激损伤^［24］。此外，R-spondin3作为Wnt通路增强子，在MASH患者晚期纤维化中呈高表达，靶向R-spondin3的抗体OMP-131R10可抑制β-catenin核易位和胶原蛋白合成，发挥抗纤维化作用，但可能干扰肝脏再生能力^［45］。天然产物如血红素可通过下调Wnt1/Wnt5a表达、抑制β-catenin/NFAT并上调GSK-3β表达，显著降低ROS并诱导HSC凋亡，从而减轻肝纤维化^［17］。中药成分人参皂苷Rg₁在NAFLD小鼠中，能抑制肝脏TGF-β1、Wnt3a、β-catenin蛋白表达，降低肝纤维化评分^［46］，而白藜芦醇则上调Wnt3a促进肝细胞增殖，修复脂肪肝损伤，抑制肝纤维化进展^［47］。GLP-1激动剂利拉鲁肽常用于糖尿病治疗，有研究发现，利拉鲁肽上调糖尿病小鼠肝脏中的Wnt/β-catenin信号通路，改善氧化应激和炎症状态，从而改善肝细胞变性和细胞凋亡^［48］。

3.2 未来药物开发的关键与创新方向

尽管现有Wnt通路调节剂在其他疾病和实验模型中展现出疗效，但应用于临床仍面临挑战。首先，器官生长发育中Wnt信号通路具有核心调节作用，且在MAFLD肝纤维化进展中表现出复杂性，直接抑制可能影响其他器官功能或肝脏再生^［49］。因此，药物有必要实现肝组织靶向递送、亚型选择或动态调节，使其在肝组织中抑制致病信号的同时保留生理功能。中药复合制剂和天然产物虽具有多靶点抗纤维化的优势，但其活性成分复杂且长期安全性评估不足，需鉴定出针对性强、安全性高的有效成分^［50］。其次，Wnt信号通路与其他信号通路的相互作用也为未来研究提供方向。例如，利拉鲁肽在改善胰岛素抵抗的同时可能协同抑制肝纤维化，体现了代谢调控与抗肝纤维化联合治疗的潜力^［48］。此外，针对MAFLD肝纤维化的多数研究仍停留在动物和细胞模型阶段，且临床研究和数据不足。但有观点指出，包括MAFLD在内的多种慢性肝病的肝纤维化在发生过程中存在一定共性，现有研究成果有望未来应用于MAFLD肝纤维化的治疗^［51］。

4 小结

在过去20年中，MAFLD的发病率和死亡率持续上升，且患病人群呈年轻化趋势；MAFLD患者的肝纤维化程度与其预后紧密相关，因此，控制甚至逆转肝纤维化是疾病长期管理的重要环节。Wnt信号通路在MAFLD相关的肝纤维化进程中扮演重要角色，因此，调节Wnt信号通路是治疗MAFLD肝纤维化的潜在新策略。目前，Wnt信号通路调节剂的抗肝纤维化作用被广泛研究，而针对MAFLD肝纤维化的研究仍处于早期阶段。尽管MAFLD肝纤维化机制具有特异性，但与其他慢性肝病肝纤维化也存在共性，如HSC活化、ECM沉积等方面，现有研究成果可能为MAFLD肝纤维化的治疗提供理论依据和技术支持。考虑到Wnt信号通路在多种组织中广泛存在且机制复杂，精准的肝靶向药物递送和特定亚型调控尤为重要。总之，Wnt信号通路在治疗MAFLD肝纤维化中仍具有应用前景，进一步阐明其在疾病进展的作用机制，将推动更加安全、有效的个体化靶向治疗策略的开发。

参考文献

[1] ESLAM M, SANYAL AJ, GEORGE J,et al. MAFLD:A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020,158(7): 1999-2014.e1. DOI: 10.1053/j.gastro.2019.11.312 .

[2] ESLAM M, FAN JG, YU ML, et al. The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic dysfunction-associated fatty liver disease[J]. Hepatol Int, 2025,19(2): 261-301. DOI:10.1007/s12072-024-10774-3 .

[3] RINELLA ME, LAZARUS JV, RATZIU V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature[J]. Ann Hepatol, 2024, 29(1): 101133. DOI:10.1016/j.aohep.2023.101133 .

[4] Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of metabolic dysfunction-associated(non- alcoholic)fatty liver disease(Version 2024)[J].J Prac Hepatol, 2024, 27(4): 494-510. DOI: 10.3760/cma.j.cn501113-20240327-00163 .

[5] 中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版)[J]. 实用肝脏病杂志, 2024, 27(4): 494-510. DOI: 10.3760/cma.j.cn501113-20240327-00163 .

[6] ISRAELSEN M, FRANCQUE S, TSOCHATZIS EA, et al. Steatotic liver disease[J]. Lancet, 2024, 404(10464): 1761-1778. DOI: 10.1016/S0140-6736(24)01811-7 .

[7] WU XN, XUE F, ZHANG N, et al. Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019[J]. BMC Public Health, 2024, 24(1): 363. DOI: 10.1186/s12889-024-17948-6 .

[8] MIAO L, TARGHER G, BYRNE CD, et al. Current status and future trends of the global burden of MASLD[J]. Trends Endocrinol Metab, 2024, 35(8): 697-707. DOI: 10.1016/j.tem.2024.02.007 .

[9] SIMON TG, ROELSTRAETE B, KHALILI H, et al. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: Results from a nationwide cohort[J]. Gut, 2021, 70(7):1375-1382. DOI: 10.1136/gutjnl-2020-322786 .

[10] SHREE HARINI K, EZHILARASAN D. Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases[J]. Hepatobiliary Pancreat Dis Int, 2023,22(4): 333-345. DOI: 10.1016/j.hbpd.2022.10.003 .

[11] PERUGORRIA MJ, OLAIZOLA P, LABIANO I, et al. Wnt-β-catenin signalling in liver development, health and disease[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(2): 121-136. DOI: 10.1038/s41575-018-0075-9 .

[12] RIM EY, CLEVERS H, NUSSE R. The Wnt pathway: From signaling mechanisms to synthetic modulators[J]. Annu Rev Biochem, 2022, 91: 571-598. DOI: 10.1146/annurev-biochem-040320-103615 .

[13] QIN K, YU M, FAN JM, et al. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk[J]. Genes Dis, 2023, 11(1): 103-134. DOI: 10.1016/j.gendis.2023.01.030 .

[14] ISHITANI T, KISHIDA S, HYODO-MIURA J, et al. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling[J]. Mol Cell Biol, 2003, 23(1): 131-139. DOI: 10.1128/MCB.23.1.131-139.2003 .

[15] SCHWABE RF, TABAS I, PAJVANI UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis[J]. Gastroenterology, 2020, 158(7): 1913-1928. DOI: 10.1053/j.gastro.2019.11.311 .

[16] BOUREBABA N, MARYCZ K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview[J]. Pharmacol Res, 2021, 170: 105739. DOI: 10.1016/j.phrs.2021.105739 .

[17] LI YQ, TANG WJ, ZHOU YJ. Role of intestinal microbiota and metabolites in the development, progression, and treatment of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2023, 39(8): 1805-1810. DOI: 10.3969/j.issn.1001-5256.2023.08.006 .

[18] 李永强, 唐文娟, 周永健. 肠道菌群及其代谢产物在非酒精性脂肪性肝病发生发展及治疗中的作用[J]. 临床肝胆病杂志, 2023, 39(8): 1805-1810. DOI: 10.3969/j.issn.1001-5256.2023.08.006 .

[19] DU JH, REN WG, ZHANG QS, et al. Heme oxygenase-1 suppresses Wnt signaling pathway in nonalcoholic steatohepatitis-related liver fibrosis[J]. Biomed Res Int, 2020, 2020: 4910601. DOI: 10.1155/2020/4910601 .

[20] WANG FX, CHEN L, KONG DS, et al. Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex[J]. Hepatology, 2024, 79(3) 606-623. DOI: 10.1097/HEP.0000000000000569 .

[21] ESMAIL MM, SAEED NM, MICHEL HE, et al. The ameliorative effect of niclosamide on bile duct ligation induced liver fibrosis via suppression of NOTCH and Wnt pathways[J]. Toxicol Lett, 2021, 347: 23-35. DOI: 10.1016/j.toxlet.2021.04.018 .

[22] PERKINS RS, SINGH R, ABELL AN, et al. The role of WNT10B in physiology and disease: A 10-year update[J]. Front Cell Dev Biol, 2023, 11: 1120365. DOI: 10.3389/fcell.2023.1120365 .

[23] XI Y, LACANNA R, MA HY, et al. A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis[J]. Cell Metab, 2022,34(9): 1377-1393.e8. DOI: 10.1016/j.cmet.2022.07.009 .

[24] MIAO JH, HUANG JW, LUO CW, et al. Klotho retards renal fibrosis through targeting mitochondrial dysfunction and cellular senescence in renal tubular cells[J]. Physiol Rep, 2021, 9(2): e14696. DOI: 10.14814/phy2.14696 .

[25] XU DN, ZHUANG SQ, CHEN HZ, et al. IL-33 regulates adipogenesis via Wnt/β-catenin/PPAR-γ signaling pathway in preadipocytes[J]. J Transl Med, 2024, 22(1): 363. DOI: 10.1186/s12967-024-05180-0 .

[26] TABAA MM EL, FAHEEM H, ELBALLAL MS, et al. The PPAR-α agonist oleoyethanolamide (OEA) ameliorates valproic acid-induced steatohepatitis in rats via suppressing Wnt3a/β-catenin and activating PGC-1α: Involvement of network pharmacology and molecular docking[J]. Eur J Pharmacol, 2025, 991:177306. DOI: 10.1016/j.ejphar.2025.177306 .

[27] MOTIZUKI M, YOKOYAMA T, SAITOH M, et al. The Snail signaling branch downstream of the TGF-β/Smad3 pathway mediates Rho activation and subsequent stress fiber formation[J]. J Biol Chem, 2024, 300(1): 105580. DOI: 10.1016/j.jbc.2023.105580 .

[28] LIU ZW, KUNA VK, XU B, et al. Wnt ligands 3a and 5a regulate proliferation and migration in human fetal liver progenitor cells[J]. Transl Gastroenterol Hepatol, 2021, 6: 56. DOI: 10.21037/tgh.2020.01.12 .

[29] KE ZL, HUANG YB, XU J, et al. Escherichia coli NF73-1 disrupts the gut-vascular barrier and aggravates high-fat diet-induced fatty liver disease via inhibiting Wnt/β-catenin signalling pathway[J]. Liver Int, 2024, 44(3): 776-790. DOI: 10.1111/liv.15823 .

[30] DONG X, LUO Y, LU S, et al. Ursodesoxycholic acid alleviates liver fibrosis via proregeneration by activation of the ID1-WNT2/HGF signaling pathway[J]. Clin Transl Med, 2021, 11(2):e296. DOI: 10.1002/ctm2.296 .

[31] CHEN T, SHI ZM, ZHAO YM, et al. LncRNA Airn maintains LSEC differentiation to alleviate liver fibrosis via the KLF2-ENOS-sGC pathway[J]. BMC Med, 2022, 20(1): 335. DOI: 10.1186/s12916-022-02523-w .

[32] DUAN JL, RUAN B, YAN XC, et al. Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice[J]. Hepatology, 2018, 68(2): 677-690. DOI: 10.1002/hep.29834 .

[33] XU T, PAN LX, LI LY, et al. microRNA-708 modulates Hepatic Stellate Cells activation and enhances extracellular matrix accumulation via direct targeting TMEM88[J]. J Cell Mol Med, 2020, 24(13): 7127-7140. DOI: 10.1111/jcmm.15119 .

[34] YUAN Y, HAN QJ, LI SY, et al. Wnt2b attenuates HSCs activation and liver fibrosis through negative regulating TLR4 signaling[J]. Sci Rep, 2017, 7(1): 3952. DOI: 10.1038/s41598-017-04374-5 .

[35] RIGUAL MDM, ANGULO-AGUADO M, ZAGORAC S, et al. Macrophages harness hepatocyte glutamate to boost liver regeneration[J]. Nature, 2025, 641(8064): 1005-1016. DOI: 10.1038/s41586-025-08778-6 .

[36] ZHANG P, LIU JL, LEE A, et al. IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis[J]. Cell Metab, 2024, 36(10): 2341-2354.e6. DOI: 10.1016/j.cmet.2024.08.012 .

[37] CHEN Y, GAO WK, SHU YY, et al. Mechanisms of ductular reaction in non-alcoholic steatohepatitis[J]. World J Gastroenterol, 2022, 28(19): 2088-2099. DOI:10.3748/wjg.v28.i19.2088 .

[38] WEI M, ZHANG CM, TIAN YJ, et al. Expression and function of WNT6: From development to disease[J]. Front Cell Dev Biol, 2020, 8: 558155. DOI: 10.3389/fcell.2020.558155 .

[39] CATALANO T, SELVAGGI F, ESPOSITO DL, et al. Infectious agents induce Wnt/β-catenin pathway deregulation in primary liver cancers[J]. Microorganisms, 2023, 11(7): 1632. DOI: 10.3390/microorganisms11071632 .

[40] SHREE HARINI K, EZHILARASAN D, MANI U. Molecular insights on intracellular Wnt/β-catenin signaling in alcoholic liver disease[J]. Cell Biochem Funct, 2024, 42(1): e3916. DOI: 10.1002/cbf.3916 .

[41] LEI ZL, YANG LX, YANG YH, et al. Activation of Wnt/β-catenin pathway causes insulin resistance and increases lipogenesis in HepG2 cells via regulation of endoplasmic reticulum stress[J]. Biochem Biophys Res Commun, 2020, 526(3): 764-771. DOI: 10.1016/j.bbrc.2020.03.147 .

[42] ASTARINI F DWI, RATNASARI N, WASITYASTUTI W. Update on non-alcoholic fatty liver disease-associated single nucleotide polymorphisms and their involvement in liver steatosis, inflammation, and fibrosis: A narrative review[J]. Iran Biomed J, 2022, 26(4): 252-268. DOI: 10.52547/ibj.3647 .

[43] QIU YY, ZHANG J, ZENG FY, et al. Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)[J]. Pharmacol Res, 2023, 192: 106786. DOI: 10.1016/j.phrs.2023.106786 .

[44] TERATANI T, TOMITA K, SUZUKI T, et al. Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis[J]. J Clin Invest, 2018, 128(4): 1581-1596. DOI: 10.1172/JCI92863 .

[45] LI F, LI MW, WANG YS. Therapeutic paradigms and potential therapies for nonalcoholic steatohepatitis[J]. J Clin Hepatol, 2024, 40(10): 2082-2086. DOI: 10.12449/JCH241025 .

[46] 李凤, 李茂微, 王雨杉. 非酒精性脂肪肝病的治疗模式和潜在疗法[J]. 临床肝胆病杂志, 2024, 40(10): 2082-2086. DOI: 10.12449/JCH241025 .

[47] EL-DERANY MO, EL-DEMERDASH E. Pyrvinium pamoate attenuates non-alcoholic steatohepatitis: Insight on hedgehog/Gli and Wnt/β-catenin signaling crosstalk[J]. Biochem Pharmacol, 2020, 177: 113942. DOI: 10.1016/j.bcp.2020.113942 .

[48] ZHANG MJ, HAUGHEY M, WANG NY, et al. Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs[J]. PLoS One, 2020,15(3): e0229445. DOI: 10.1371/journal.pone.0229445 .

[49] HE WW, YANG RG, LUO TT. Effect of ginsenoside Rg₁ on liver fibrosis in mice with non-alcoholic fatty liver disease[J]. J Chin Med Mater, 2021, 44(5): 1208-1212. DOI: 10.13863/j.issn1001-4454.2021.05.032 .

[50] 贺微微, 杨仁国, 罗婷婷. 人参皂苷Rg₁对非酒精性脂肪性肝病小鼠肝纤维化的作用[J]. 中药材, 2021, 44(5): 1208-1212. DOI: 10.13863/j.issn1001-4454.2021.05.032 .

[51] LI QJ, GONG YQ, WANG Y, et al. Sirt1 promotes the restoration of hepatic progenitor cell (HPC)-mediated liver fatty injury in NAFLD through activating the Wnt/β-catenin signal pathway[J]. Front Nutr, 2021, 8: 791861. DOI: 10.3389/fnut.2021.791861 .

[52] YU J, ZHAO Y, XU LL,et al. Liraglutide attenuates hepatic oxidative stress, inflammation, and apoptosis in streptozotocin-induced diabetic mice by modulating the Wnt/β-catenin signaling pathway[J]. Mediators Inflamm, 2023, 2023: 8974960. DOI: 10.1155/2023/8974960 .

[53] XUE C, CHU QF, SHI QM, et al. Wnt signaling pathways in biology and disease: Mechanisms and therapeutic advances[J]. Signal Transduct Target Ther, 2025, 10(1): 106. DOI: 10.1038/s41392-025-02142-w .

[54] ZHENG GG, LIN SQ, WANG SJ, et al. Regulation of natural products on Wnt/β-catenin signaling pathway in diseases[J]. Am J Chin Med, 2025, 53(3): 709-735. DOI: 10.1142/S0192415X25500272 .

[55] DUSPARA K, BOJANIC K, PEJIC JI, et al. Targeting the Wnt signaling pathway in liver fibrosis for drug options: An update[J]. J Clin Transl Hepatol, 2021, 9(6): 960-971. DOI: 10.14218/JCTH.2021.00065 .

基金资助

甘肃省自然科学基金(23JRRA0939)

兰州市人才创新创业项目(2019-RC-33)