中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 42 Issue 8
Aug.  2026
Turn off MathJax
Article Contents

Regulatory role and mechanism of lactate in metabolic dysfunction-associated fatty liver disease

DOI: 10.12449/JCH260829
Research funding:

General Project of National Natural Science Foundation of China (32573324);

General Project of National Natural Science Foundation of China (32272965)

More Information
  • Corresponding author: Yang Jiancheng, syndyjc@syau.edu.cn (ORCID: 0000-0002-4509-0893)
  • Received Date: 2025-12-10
  • Accepted Date: 2026-02-09
  • Published Date: 2026-08-25
  • Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease with a persistently high prevalence rate worldwide. Its pathogenesis involves metabolic disorders in multiple systems, and there is still a lack of a complete theoretical regulatory framework. Lactate was once regarded as a terminal metabolic waste product of the glycolytic pathway; however, studies in recent years have been exploring its biological functions as a key signaling molecule, and the close association between dysregulated lactate metabolism and the development and progression of MAFLD has gradually become a research hotspot in the field of metabolic liver diseases. This article systematically introduces the core pathways and regulatory patterns of lactate metabolism, elaborates on the overall functional characteristics of lactate in the development and progression of MAFLD, and reviews the molecular mechanisms by which lactate mediates hepatic lipid metabolism disorders and drives inflammatory cascades through epigenetic regulatory mechanisms such as protein lactylation. In addition, it briefly describes the potential effect of lactate in modulating liver metabolic homeostasis via the gut-liver axis and summarizes the latest research advances in lactate metabolism and MAFLD. This article highlights that targeting lactate metabolic pathways is a critical entry point for deepening the understanding of the pathophysiological mechanisms of MAFLD, and it points out that non-canonical regulatory modes represented by lactylation are key breakthrough directions for future research. It also proposes that developing early diagnostic biomarkers and intervention targets for MAFLD based on the lactate metabolic network holds important theoretical value and clinical translation potential.

     

  • loading
  • [1]
    Huang D Q, Singal A G, Kono Y, et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer[J]. Cell Metab, 2022, 34( 7): 969- 977. DOI: 10.1016/j.cmet.2022.05.003.
    [2]
    Zhou Zhijia, Li Xinyue, Zheng Chao, et al. Advances in traditional Chinese medicine treatment of liver fibrosis in metabolic associated fatty liver disease[J]. J Clin Hepatol, 2025, 41( 10): 1968- 1974. DOI: 10.12449/JCH251002.

    周志佳, 李新月, 郑超, 等. 代谢相关脂肪性肝病肝纤维化的中医药治疗进展[J]. 临床肝胆病杂志, 2025, 41( 10): 1968- 1974. DOI: 10.12449/JCH251002.
    [3]
    Paik J M, Golabi P, Younossi Y, et al. Changes in the global burden of chronic liver diseases from 2012 to 2017: The growing impact of NAFLD[J]. Hepatology, 2020, 72( 5): 1605- 1616. DOI: 10.1002/hep.31173.
    [4]
    Devarbhavi H, Asrani S K, Arab J P, et al. Global burden of liver disease: 2023 update[J]. J Hepatol, 2023, 79( 2): 516- 537. DOI: 10.1016/j.jhep.2023.03.017.
    [5]
    Wang F S, Fan J G, Zhang Z, et al. The global burden of liver disease: The major impact of China[J]. Hepatology, 2014, 60( 6): 2099- 2108. DOI: 10.1002/hep.27406.
    [6]
    Oyabambi A O, Olaniyi K S, Soladoye A O, et al. Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats[J]. Environ Toxicol Pharmacol, 2020, 80: 103452. DOI: 10.1016/j.etap.2020.103452.
    [7]
    Wu G L, Dai Y F, Yan Y H, et al. The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs[J]. Eur J Pharmacol, 2022, 924: 174959. DOI: 10.1016/j.ejphar.2022.174959.
    [8]
    Rho H, Terry A R, Chronis C, et al. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis[J]. Cell Metab, 2023, 35( 8): 1406- 1423. DOI: 10.1016/j.cmet.2023.06.013.
    [9]
    Drolz A, Horvatits T, Rutter K, et al. Lactate improves prediction of short-term mortality in critically ill patients with cirrhosis: A multinational study[J]. Hepatology, 2019, 69( 1): 258- 269. DOI: 10.1002/hep.30151.
    [10]
    Nalbandian M, Takeda M. Lactate as a signaling molecule that regulates exercise-induced adaptations[J]. Biology, 2016, 5( 4): 38. DOI: 10.3390/biology5040038.
    [11]
    Robergs R A, McNulty C R, Minett G M, et al. Lactate, not lactic acid, is produced by cellular cytosolic energy catabolism[J]. Physiology(Bethesda), 2018, 33( 1): 10- 12. DOI: 10.1152/physiol.00033.2017.
    [12]
    Talasniemi J P, Pennanen S, Savolainen H, et al. Analytical investigation: Assay of D-lactate in diabetic plasma and urine[J]. Clin Biochem, 2008, 41( 13): 1099- 1103. DOI: 10.1016/j.clinbiochem.2008.06.011.
    [13]
    Fantin V R, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance[J]. Cancer Cell, 2006, 9( 6): 425- 434. DOI: 10.1016/j.ccr.2006.04.023.
    [14]
    Fang Chunyao, Zhou Suiqing, Yu Kai, et al. Research progress of lactate metabolism and lactylation in the diagnosis and treatment of hepatocellular carcinoma[J]. Chin J Dig Surg, 2026, 25( 4): 592- 597. DOI: 10.3760/cma.j.cn115610-20260224-00090.

    房春耀, 周岁清, 俞锴, 等. 乳酸代谢与乳酸化修饰在肝细胞癌诊疗中的研究进展[J]. 中华消化外科杂志, 2026, 25( 4): 592- 597. DOI: 10.3760/cma.j.cn115610-20260224-00090.
    [15]
    DeBerardinis R J, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis[J]. Proc Natl Acad Sci U S A, 2007, 104( 49): 19345- 19350. DOI: 10.1073/pnas.0709747104.
    [16]
    Bennis Y, Bodeau S, Batteux B, et al. A study of associations between plasma metformin concentration, lactic acidosis, and mortality in an emergency hospitalization context[J]. Crit Care Med, 2020, 48( 12): e1194- e1202. DOI: 10.1097/CCM.0000000000004589.
    [17]
    Jha M K, Lee I K, Suk K. Metabolic reprogramming by the pyruvate dehydrogenase kinase-lactic acid axis: Linking metabolism and diverse neuropathophysiologies[J]. Neurosci Biobehav Rev, 2016, 68: 1- 19. DOI: 10.1016/j.neubiorev.2016.05.006.
    [18]
    Soreze Y, Boutron A, Habarou F, et al. Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase[J]. Orphanet J Rare Dis, 2013, 8: 192. DOI: 10.1186/1750-1172-8-192.
    [19]
    Emhoff C A, Messonnier L A, Horning M A, et al. Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold[J]. J Appl Physiol(1985), 2013, 114( 3): 297- 306. DOI: 10.1152/japplphysiol.01202.2012.
    [20]
    Wang T X, Chen K, Yao W L, et al. Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance[J]. J Hepatol, 2021, 74( 5): 1038- 1052. DOI: 10.1016/j.jhep.2020.11.028.
    [21]
    Zhang L L, Xin C H, Wang S, et al. Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle[J]. Sci Adv, 2024, 10( 26): eadn4508. DOI: 10.1126/sciadv.adn4508.
    [22]
    Eskuri M, Kemi N, Kauppila J H. Monocarboxylate transporters 1 and 4 and MTCO1 in gastric cancer[J]. Cancers, 2021, 13( 9): 2142. DOI: 10.3390/cancers13092142.
    [23]
    Hu J Y, Cai M, Liu Y R, et al. The roles of GRP81 as a metabolic sensor and inflammatory mediator[J]. J Cell Physiol, 2020, 235( 12): 8938- 8950. DOI: 10.1002/jcp.29739.
    [24]
    Madaan A, Nadeau-Vallée M, Rivera J C, et al. Lactate produced during labor modulates uterine inflammation via GPR81(HCA1)[J]. Am J Obstet Gynecol, 2017, 216( 1): 60. DOI: 10.1016/j.ajog.2016.09.072.
    [25]
    Sun Z R, Han Y, Song S B, et al. Activation of GPR81 by lactate inhibits oscillatory shear stress-induced endothelial inflammation by activating the expression of KLF2[J]. IUBMB Life, 2019, 71( 12): 2010- 2019. DOI: 10.1002/iub.2151.
    [26]
    Laroche S, Stil A, Germain P, et al. Participation of L-lactate and its receptor HCAR1/GPR81 in neurovisual development[J]. Cells, 2021, 10( 7): 1640. DOI: 10.3390/cells10071640.
    [27]
    Wan Juan, Cheng Chunfang, Tang Shan, et al. Research progress of lactate as signal molecule[J]. Chin J Cell Biol, 2022, 44( 10): 1980- 1986. DOI: 10.11844/cjcb.2022.10.0011.

    万娟, 程春芳, 唐珊, 等. 乳酸作为信号分子作用的研究进展[J]. 中国细胞生物学学报, 2022, 44( 10): 1980- 1986. DOI: 10.11844/cjcb.2022.10.0011.
    [28]
    Ahmed K, Tunaru S, Tang C, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81[J]. Cell Metab, 2010, 11( 4): 311- 319. DOI: 10.1016/j.cmet.2010.02.012.
    [29]
    Chen S Y, Zhou L, Sun J Q, et al. The role of cAMP-PKA pathway in lactate-induced intramuscular triglyceride accumulation and mitochondria content increase in mice[J]. Front Physiol, 2021, 12: 709135. DOI: 10.3389/fphys.2021.709135.
    [30]
    Zhang D, Tang Z Y, Huang H, et al. Metabolic regulation of gene expression by histone lactylation[J]. Nature, 2019, 574( 7779): 575- 580. DOI: 10.1038/s41586-019-1678-1.
    [31]
    Li H, Li Z Y, Chen L, et al. PDHA1-mediated H3K18 lactylation is involved in arsenic-induced nonalcoholic fatty liver disease by activating the CD36-NLRP3 inflammasome axis[J]. J Hazard Mater, 2025, 498: 139852. DOI: 10.1016/j.jhazmat.2025.139852.
    [32]
    Kumar S, Sahu N, Jawaid T, et al. Dual role of lactate in human health and disease[J]. Front Physiol, 2025, 16: 1621358. DOI: 10.3389/fphys.2025.1621358.
    [33]
    Pohanka M. D-lactic acid as a metabolite: Toxicology, diagnosis, and detection[J]. Biomed Res Int, 2020, 2020: 3419034. DOI: 10.1155/2020/3419034.
    [34]
    Lazzeri C, Gensini G F, Sori A, et al. Dynamic behaviour of lactate values during mild hypothermia in patients with cardiac arrest[J]. Eur Heart J Acute Cardiovasc Care, 2014, 3( 2): 176- 182. DOI: 10.1177/2048872613514014.
    [35]
    Scheiner B, Lindner G, Reiberger T, et al. Acid-base disorders in liver disease[J]. J Hepatol, 2017, 67( 5): 1062- 1073. DOI: 10.1016/j.jhep.2017.06.023.
    [36]
    Ma Y L, Ke J F, Wang J W, et al. Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: A real-world study[J]. Front Endocrinol, 2023, 14: 1133991. DOI: 10.3389/fendo.2023.1133991.
    [37]
    Yu L, Bao S M, Zhu F, et al. Serum lactate dehydrogenase is a novel predictor for the severity in the patients with MAFLD: A cross-sectional study in Hefei, China[J]. Diabetes Metab Syndr Obes, 2025, 18: 345- 361. DOI: 10.2147/DMSO.S492153.
    [38]
    Yao Z Y, Gong Y, Chen W B, et al. Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice[J]. Nat Metab, 2023, 5( 10): 1706- 1725. DOI: 10.1038/s42255-023-00896-7.
    [39]
    Tao R Y, Stöhr O, Tok O, et al. Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance[J]. Nat Commun, 2025, 16( 1): 11595. DOI: 10.1038/s41467-025-66296-5.
    [40]
    Lin Y J, Bai M J, Wang S, et al. Lactate is a key mediator that links obesity to insulin resistance via modulating cytokine production from adipose tissue[J]. Diabetes, 2022, 71( 4): 637- 652. DOI: 10.2337/db21-0535.
    [41]
    Gou Y N, Li A H, Dong X Y, et al. Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease[J]. Genes Dis, 2025, 12( 4): 101554. DOI: 10.1016/j.gendis.2025.101554.
    [42]
    Liu Y, Zhou R, Guo Y F, et al. Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining[J]. Cell Metab, 2025, 37( 4): 824- 841. DOI: 10.1016/j.cmet.2024.12.005.
    [43]
    Wang X Y, Chen H, Zhu W F, et al. Akebia trifoliata extracts attenuate liver injury via gut-liver axis in a murine model of nonalcoholic fatty liver disease with low-grade colitis[J]. Food Res Int, 2025, 208: 116202. DOI: 10.1016/j.foodres.2025.116202.
    [44]
    Song W, Hu J H, Zhu L N, et al. Inulin alleviates HFD-induced NAFLD by hepatic macrophage polarization and lipid metabolism via gut-liver axis[J]. Food Sci Hum Wellness, 2025, 14( 2): 9250040. DOI: 10.26599/fshw.2024.9250040.
    [45]
    Kuang J L, Wang J Y, Li Y T, et al. Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis[J]. Cell Metab, 2023, 35( 10): 1752- 1766. DOI: 10.1016/j.cmet.2023.07.011.
    [46]
    Zhao H, Zhou J, Yuan L, et al. Exploring the alleviating effects of Bifidobacterium metabolite lactic acid on non-alcoholic steatohepatitis through the gut-liver axis[J]. Front Microbiol, 2025, 15: 1518150. DOI: 10.3389/fmicb.2024.1518150.
    [47]
    Zhu Y Y, Dong X, Zhou H, et al. Gut microbiota colonization in early life influences susceptibility to adulthood hepatic lipid accumulation in high-fat-diet-fed mice[J]. Adv Sci(Weinh), 2025, 12( 21): e2412827. DOI: 10.1002/advs.202412827.
    [48]
    Sarkar S, Saha P, Seth R K, et al. Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease[J]. Comp Biochem Physiol C Toxicol Pharmacol, 2020, 238: 108854. DOI: 10.1016/j.cbpc.2020.108854.
    [49]
    Gao R X, Li Y, Xu Z M, et al. Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease[J]. Hepatology, 2023, 78( 6): 1800- 1815. DOI: 10.1097/HEP.0000000000000279.
    [50]
    Jeppesen J B, Mortensen C, Bendtsen F, et al. Lactate metabolism in chronic liver disease[J]. Scand J Clin Lab Invest, 2013, 73( 4): 293- 299. DOI: 10.3109/00365513.2013.773591.
    [51]
    Ha T S, Shin T G, Jo I J, et al. Lactate clearance and mortality in septic patients with hepatic dysfunction[J]. Am J Emerg Med, 2016, 34( 6): 1011- 1015. DOI: 10.1016/j.ajem.2016.02.053.
    [52]
    Li J, Wang T X, Xia J, et al. Enzymatic and nonenzymatic protein acetylations control glycolysis process in liver diseases[J]. FASEB J, 2019, 33( 11): 11640- 11654. DOI: 10.1096/fj.201901175R.
    [53]
    Dufour J F, Anstee Q M, Bugianesi E, et al. Current therapies and new developments in NASH[J]. Gut, 2022, 71( 10): 2123- 2134. DOI: 10.1136/gutjnl-2021-326874.
    [54]
    Roland C L, Arumugam T, Deng D F, et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival[J]. Cancer Res, 2014, 74( 18): 5301- 5310. DOI: 10.1158/0008-5472.CAN-14-0319.
    [55]
    Li J Y, Chen X C, Song S Y, et al. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD[J]. Cell Rep, 2025, 44( 3): 115350. DOI: 10.1016/j.celrep.2025.115350.
    [56]
    Jiao Q L, Ren Y D, Teng X Y, et al. Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression[J]. Hepatol Int, 2026, 20( 3): 646- 663. DOI: 10.1007/s12072-025-10978-1.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (9) PDF downloads(0) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return