International Research in Chinese Medicine
International Research in Chinese Medicine. 2026; 6: (2) ; 10.12208/j.ircm.20260035 .
总浏览量: 38
济宁医学院中西医结合学院 山东济宁
*通讯作者： 刘媛,单位：济宁医学院中西医结合学院 山东济宁; ；
肝纤维化（Hepatic fibrosis, HF）是慢性肝脏疾病进程中关键的病理阶段，肝星状细胞（HSCs）的糖酵解代谢重编程与HF的发生发展密切相关。活化的HSCs在富氧条件下表现出类似肿瘤细胞的“Warburg效应”，优先通过有氧糖酵解快速供能，以满足其增殖、迁移和分泌细胞外基质等高能量需求。本文系统综述了HSCs糖酵解代谢重编程的分子机制及其在HF中的作用，重点探讨了TGF-β/Smad、Wnt/β-catenin、HIF-1α等信号通路以及己糖激酶-2、磷酸果糖激酶-1、乳酸脱氢酶A等关键酶对HSCs活化的调控作用，并分析了靶向糖酵解代谢的潜在治疗策略。这些研究进展不仅深化了对HF发病机制的认识，也为开发新型抗纤维化药物提供了多靶点干预的理论依据。
Hepatic fibrosis (HF) represents a key pathological stage during the progression of chronic liver diseases. Glycolytic metabolic reprogramming of hepatic stellate cells (HSCs) is closely related to the development of HF. Under oxygen-rich conditions, activated HSCs exhibit the Warburg effect similar to tumor cells, which preferentially obtains rapid energy supply through aerobic glycolysis to meet high energy demands for proliferation, migration and extracellular matrix secretion. In this paper, we systematically reviewed the molecular mechanisms of glycolytic metabolic reprogramming in HSCs and its role in HF, focused on the regulatory impacts of signaling pathways including TGF-β/Smad, Wnt/β-catenin and HIF-1α, as well as major glycolytic key enzymes such as hexokinase-2, phosphofructokinase-1 and lactate dehydrogenase A on HSCs activation, and analyzed the potential therapeutic strategies targeting glycolytic metabolism. These research advances not only deepen the understanding of the pathogenesis of HF, but also provide a multi-target theoretical basis for the development of novel antifibrotic drugs.
[1] Wang X, Wang Y, Li X, Qin S, Xu J, Xie J. Exploration of new therapeutic targets for viral hepatic fibrosis, alcoholic hepatic fibrosis, and non-alcoholic hepatic fibrosis. Ann Transl Med. 2022;10(16):886.
[2] Zamani M, Alizadeh-Tabari S, Ajmera V, Singh S, Murad MH, Loomba R. Global Prevalence of Advanced Liver Fibrosis and Cirrhosis in the General Population: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2024 Aug 30:S1542-3565(24)00790-0.
[3] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
[4] Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D. Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression. Signal Transduct Target Ther. 2020;5(1): 242. Published 2020 Oct 19.
[5] Schuppan D. Liver fibrosis: Common mechanisms and antifibrotic therapies. Clin Res Hepatol Gastroenterol. 2015;39 Suppl 1:S51-S59.
[6] Senoo H. Structure and function of hepatic stellate cells. Med Electron Microsc. 2004;37(1):3-15.
[7] Hendriks HF, Verhoofstad WA, Brouwer A, de Leeuw AM, Knook DL. Perisinusoidal fat-storing cells are the main vitamin A storage sites in rat liver. Exp Cell Res. 1985; 160(1):138-149.
[8] Arriazu E, Ruiz de Galarreta M, Cubero FJ, et al. Extracellular matrix and liver disease. Antioxid Redox Signal. 2014;21(7):1078-1097.
[9] Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011;25(2):195-206.
[10] Cong M, Iwaisako K, Jiang C, Kisseleva T. Cell signals influencing hepatic fibrosis. Int J Hepatol. 2012;2012: 158547.
[11] Choi SS，Diehl AM. Epithelial-to-mesenchymal transitions in the liver [J]. Hepatology,2009,50(6):2007.
[12] Yan P, Liu J, Li Z, et al. Glycolysis reprogramming in idiopathic pulmonary fibrosis: unveiling the mystery of lactate in the lung[J]. International journal of molecular sciences, 2023, 25(1): 315.
[13] Wang F, Jia Y, Li M, et al. Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells. Cell Commun Signal. 2019;17(1):11. Published 2019 Feb 11.
[14] Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells. 2019;9(1):24. Published 2019 Dec 20.
[15] Saito A, Horie M, Nagase T. TGF-β Signaling in Lung Health and Disease. Int J Mol Sci. 2018;19(8):2460. Published 2018 Aug 20.
[16] Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb Perspect Biol. 2016 May 2;8(5):a021873.
[17] Budi E H, Duan D, Derynck R. Transforming growth factor-β receptors and Smads: regulatory complexity and functional versatility[J]. Trends in cell biology, 2017, 27(9): 658-672.
[18] Ji Z, Siu WS, Dueñas ME, Müller L, Trost M, Carvalho P. Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex. Nat Commun. 2025 Apr 11;16(1):3474.
[19] 方萌.复方芪参提取物调节miR-145/miR-21与pSmad3C/pSmad3L串话发挥抗肝细胞癌作用[D].安徽医科大学,2018.
[20] 高利超,徐兵,刘永安,等.三七皂苷R1抑制TGF-β1/Smad3信号传导对糖尿病肾病大鼠肾脏纤维化和炎症细胞因子的调节作用研究[J].中国免疫学杂志,2020, 36(10):1188-1193.
[21] Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022 Jan 3;7(1):3.
[22] Wang F, Chen L, Kong D, et al. Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex. Hepatology. 2024;79(3): 606-623.
[23] 贾文茜.CD73通过Wnt/β-catenin通路调节肝星状细胞的活化与增殖的研究[D].安徽医科大学,2021.
[24] Semenza G L, Jiang B-H, Leung S W, et al. Hypoxia Response Elements in the Aldolase A, Enolase 1, and Lactate Dehydrogenase A Gene Promoters Contain Essential Binding Sites for Hypoxia-inducible Factor 1[J]. Journal of Biological Chemistry, 1996, 271(51): 32529-32537.
[25] Wang Y, Huang Y, Guan F, et al. Hypoxia-inducible factor-1alpha and MAPK co-regulate activation of hepaticstellate cells upon hypoxia stimulation. PLOS ONE 2013, 8(9): e74051.
[26] Copple BL, Bai S, Burgoon LD, et al. Hypoxia-inducible factor-1alpha regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis. LIVER INT 2011, 31(2): 230-244.
[27] Thambyrajah R, Maqueda M, Neo WH, et al. Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate. Nat Commun. 2024;15(1):1604. Published 2024 Feb 21.
[28] 白雅洁,杨柳青,范钦,等.铁皮石斛多糖通过上皮间质转化和Notch信号通路体外抗肝纤维化作用机制[J].中国临床药理学与治疗学,2026,31(03):337-343.
[29] 杨子懿,侯玉宁,刘彦,等.肝纤维化进程中肝窦内皮细胞与肝星状细胞互作机制的研究进展[J/OL].生理学报,1-33[2026-05-04]
[30] 谈君,郭继岑,朱统宁,等.Notch信号通路在肝纤维化中的作用机制及中医药干预进展[J].云南中医中药杂志, 2025,46(11):93-97.
[31] 王俊青,黄林生,余惠凡,等.Hippo-YAP/TAZ信号通路在器官纤维化中的作用[J].中南大学学报(医学版),2024, 49(09):1509-1516.
[32] 姚硕,李源,段超,等.白术内酯Ⅲ调节Hippo/YAP信号通路对非酒精性脂肪肝大鼠肝纤维化的影响[J].河北医药,2024,46(21):3212-3216+3221.
[33] 李明奇,王映荷,张晨璐,等.基于Hippo/YAP通路研究槲皮素体内外抗肝纤维化作用[J].华西药学杂志,2026,41(02): 163-168.
[34] 美丽·哈依吾拉,刘兰,陈艺丹,等.虾青素调节SphK1/S1P信号通路对乙型肝炎大鼠肝功能及肝纤维化的影响[J/OL].中国热带医学,1-13[2026-05-07].
[35] 王燕,肖雄,郭峰,等.和血柔肝方对肝纤维化大鼠SphK1/S1P/S1PR信号通路的影响[J].中国中医药信息杂志,2022,29(03):85-91.
[36] 吴俊林,徐波.肉桂醛通过抑制SphK1、S1P信号通路减轻非酒精性脂肪肝大鼠肝纤维化[J].广州中医药大学学报,2025,42(09):2288-2294.
[37] 张焕婷,刘玉凤,苏春芝,等.黄连素调节SphK1/S1P信号通路对乙型肝炎大鼠肝纤维化的影响[J].药物生物技术,2025,32(02):161-167.
[38] 田萌媛.基于JAK2/STAT3信号通路探讨舒肝化癥方防治肝纤维化的作用机制[D].甘肃中医药大学,2024.
[39] 王咏兰.基于JAK2/STAT3信号通路探究鬼箭羽醇提物抗CCl4诱导C57BL/6J小鼠肝纤维化作用机制[D].湖北民族大学,2023.
[40] 刘玉凤,张金丽,苏春芝,等.石蒜碱通过抑制JAK2/STAT3信号通路抑制HBV诱发肝纤维化[J].中国老年学杂志,2025,45(13):3205-3209.
[41] Irwin DM, Tan H. Molecular evolution of the vertebrate hexokinase gene family: Identification of a conserved fifth vertebrate hexokinase gene. Comp Biochem Physiol Part D Genomics Proteomics. 2008;3(1):96-107.
[42] Rho H, Terry AR, Chronis C, Hay N. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab. 2023;35(8):1406-1423.e8.
[43] Tan VP, Miyamoto S. HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection. Autophagy. 2015;11(6):963-964.
[44] Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H. Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives. Mech Ageing Dev. 2021;199:111572.
[45] Mathupala SP, Ko YH, Pedersen PL. Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene. 2006;25(34):4777-4786.
[46] 郭舜,石磊,张松,等. 黄芩素通过调控糖酵解及谷氨酰胺代谢抑制肝癌细胞能量代谢[J]. 中国药师,2021,24(12): 2154-2159.
[47] 王洁,孟军,曾亚琦,等.伊犁马PFKM基因表达及酶活性分析[J].新疆农业科学,2022,59(11):2758-2764.
[48] Kim NH, Cha YH, Lee J, et al. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nat Commun. 2017;8:14374. Published 2017 Feb 8.
[49] Huang Y, Xiong C, Wang C, et al. p53-responsive CMBL reprograms glucose metabolism and suppresses cancer development by destabilizing phosphofructokinase PFKP. Cell Rep. 2023;42(11):113426.
[50] Brooks GA, Dubouchaud H, Brown M, Sicurello JP, Butz CE. Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle. Proc Natl Acad Sci U S A. 1999;96(3):1129-1134.
[51] 崔智.ANP32A与LDHA相互作用促进肝细胞癌细胞增殖并抑制其铁死亡的机制研究[D].桂林医科大学,2025.
[52] Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor. Brain Pathol. 2016;26(1):3-17.
[53] Yadav S, Pandey SK, Kumar A, Kujur PK, Singh RP, Singh SM. Antitumor and chemosensitizing action of 3-bromopyruvate: Implication of deregulated metabolism. Chem Biol Interact. 2017;270:73-89.
[54] Shoshan MC. 3-Bromopyruvate: targets and outcomes. J Bioenerg Biomembr. 2012;44(1):7-15.
[55] Pilkis SJ, el-Maghrabi MR, Claus TH. Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics. Diabetes Care. 1990;13(6):582-599.
[56] Thirusangu P, Ray U, Sarkar Bhattacharya S, et al. PFKFB3 regulates cancer stemness through the hippo pathway in small cell lung carcinoma. Oncogene. 2022;41(33):4003-4017.
[57] Xiang XH, Jiang TP, Zhang S, et al. Pirfenidone inhibits proliferation, arrests the cell cycle, and downregulates heat shock protein-47 and collagen type I in rat hepatic stellate cells in vitro. Mol Med Rep. 2015;12(1):309-314.
[58] 李雪莹. 吡非尼酮通过糖酵解途径改善肝纤维化的研究[D]. 贵阳: 贵州医科大学, 2023.