Lactic acid and Lactylation in the Progression of Pulmonary Fibrosis

Abstract

Pulmonary fibrosis (PF) is a progressive and irreversible interstitial lung disease that is characterized by destruction of alveolar architecture, excessive proliferation of fibroblasts, and aberrant deposition of extracellular matrix (ECM) but the precise pathogenesis has yet to be fully elucidated. Although traditionally regarded as the terminal metabolite of glycolysis, lactate has been reappreciated, especially following the rise of metabolic reprogramming concepts after the Warburg effect, as an important signaling molecule capable of actively regulating diverse cellular functions. Among these cellular functions, the lactate-induced post-translational modification (PTM), known as lactylation, offers a new perspective for understanding the broad biological actions of lactate beyond metabolism. Notably, the pathologic microenvironment of PF is characterized by widespread metabolic reprogramming and lactate accumulation, suggesting that lactate and lactate-mediated lactylation may serve key roles in disease progression by regulating pro-fibrotic gene expression and influencing fibroblast activation and differentiation. Therefore, this review focuses on how lactylation functions as a bridge linking metabolic reprogramming to fibrotic phenotypes in PF and the translational potential as a novel therapeutic target is discussed.

Keywords

Eraser / lactate shuttle / lactic acid / lactylation / metabolic reprogramming / pulmonary fibrosis / reader / writer

References

[1] Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017; 389(10082): 1941-52. [PMID: 28365056 DOI: 10.1016/s0140-6736(17)30866-8]

[2] Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018; 378(19): 1811-23. [PMID: 29742380 DOI: 10.1056/NEJMra1705751]

[3] Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2001; 3(1): 3. [PMID: 11806838 DOI: 10.1186/rr175]

[4] King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378(9807): 1949-61. [PMID: 21719092 DOI: 10.1016/s0140-6736(11)60052-4]

[5] Cheng D, Zheng D, Jiang M, Jin Y, Liu R, et al. Inhibition of iron ion accumulation alleviates polystyrene nanoplastics-induced pulmonary fibroblast proliferation and activation. Int Immunopharmacol 2025; 164: 115367. [PMID: 40811949 DOI: 10.1016/j.intimp.2025.115367]

[6] Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 2006; 103(35): 13180-5. [PMID: 16924102 DOI: 10.1073/pnas.0605669103]

[7] Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, et al. The myofibroblast: one function, multiple origins. Am J Pathol 2007; 170(6): 1807-16. [PMID: 17525249 DOI: 10.2353/ajpath.2007.070112]

[8] Long H, Lichtnekert J, Andrassy J, Schraml BU, Romagnani P, et al. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy. Front Immunol 2023; 14: 1194988. [PMID: 37868987 DOI: 10.3389/fimmu.2023.1194988]

[9] JanWillem D, Lin C, Moog S, Jaillet M, Castier Y, et al. CCAAT/enhancer binding protein delta (C/EBPδ) deficiency does not affect bleomycin-induced pulmonary fibrosis. J Clin Transl Res 2018; 3(Suppl 2): 358-65. [PMID: 30873483 DOI: 10.18053/JCTRES.03.2017S2.004]

[10] Xie N, Tan Z, Banerjee S, Cui H, Ge J, et al. Glycolytic reprogramming in myofibroblast differentiation and lung fibrosis. Am J Respir Crit Care Med 2015; 192(12): 1462-74. [PMID: 26284610 DOI: 10.1164/rccm.201504-0780OC]

[11] Kottmann RM, Kulkarni AA, Smolnycki KA, Lyda E, Dahanayake T, et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β. Am J Respir Crit Care Med 2012; 186(8): 740-51. [PMID: 22923663 DOI: 10.1164/rccm.201201-0084OC]

[12] Yan P, Liu J, Li Z, Wang J, Zhu Z, et al. Glycolysis reprogramming in idiopathic pulmonary fibrosis: unveiling the mystery of lactate in the lung. Int J Mol Sci 2023; 25(1): 315. [PMID: 38203486 DOI: 10.3390/ijms25010315]

[13] Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513(7519): 559-63. [PMID: 25043024 DOI: 10.1038/nature13490]

[14] Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007; 109(9): 3812- 9. [PMID: 17255361 DOI: 10.1182/blood-2006-07-035972]

[15] Hong H, Su J, Zhang Y, Xu G, Huang C, et al. A novel role of lactate: promotion of Akt-dependent elongation of microglial process. Int Immunopharmacol 2023; 119: 110136. [PMID: 37075668 DOI: 10.1016/j.intimp.2023.110136]

[16] Zhao Y, Jiang J, Zhou P, Deng K, Liu Z, et al. H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem Pharmacol 2024; 222: 116120. [PMID: 38461905 DOI: 10.1016/j.bcp.2024.116120]

[17] Zhang D, Tang Z, Huang H, Zhou G, Cui C, et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019; 574(7779): 575-80. [PMID: 31645732 DOI: 10.1038/s41586-019-1678-1]

[18] Wan L, Zhang H, Liu J, He Q, Zhao J, et al. Lactylation and human disease. Expert Rev Mol Med 2025; 27: e10. [PMID: 39895568 DOI: 10.1017/erm.2025.3]

[19] Xiang T, Wang X, Huang S, Zhou K, Fei S, et al. Inhibition of PKM2 by shikonin impedes TGF-β1 expression by repressing histone lactylation to alleviate renal fibrosis. Phytomedicine 2025; 136: 156324. [PMID: 39700636 DOI: 10.1016/j.phymed.2024.156324]

[20] Zong Z, Xie F, Wang S, Wu X, Zhang Z, et al. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell 2024; 187(10): 2375-92.e33. [PMID: 38653238 DOI: 10.1016/j.cell.2024.04.002]

[21] Nickel GA, Pederson NJ, Faheem, Yang Z, Bulf J, et al. Sirtuin 6 is a histone delactylase. J Biol Chem 2025; 301(12): 110795. [PMID: 41062064 DOI: 10.1016/j.jbc.2025.110795]

[22] Yang Y, Luo N, Gong Z, Zhou W, Ku Y, et al. Lactate and lysine lactylation of histone regulate transcription in cancer. Heliyon 2024; 10(21): e38426. [PMID: 39559217 DOI: 10.1016/j.heliyon.2024.e38426]

[23] Merkuri F, Rothstein M, Simoes-Costa M. Histone lactylation couples cellular metabolism with developmental gene regulatory networks. Nat Commun 2024; 15(1): 90. [PMID: 38167340 DOI: 10.1038/s41467-023-44121-1]

[24] Li J, Zeng G, Zhang Z, Wang Y, Shao M, et al. Urban airborne PM_2.5 induces pulmonary fibrosis through triggering glycolysis and subsequent modification of histone lactylation in macrophages. Ecotoxicol Environ Saf 2024; 273: 116162. [PMID: 38458067 DOI: 10.1016/j.ecoenv.2024.116162]

[25] Apostolova P, Pearce EL. Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment. Trends Immunol 2022; 43(12): 969-77. [PMID: 36319537 DOI: 10.1016/j.it.2022.10.005]

[26] Li X, Yang Y, Zhang B, Lin X, Fu X, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther 2022; 7(1): 305. [PMID: 36050306 DOI: 10.1038/s41392-022-01151-3]

[27] Wu D, Wang S, Wang F, Zhang Q, Zhang Z, et al. Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension. J Transl Med 2024; 22(1): 738. [PMID: 39103838 DOI: 10.1186/s12967-024-05543-7]

[28] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029-33. [PMID: 19460998 DOI: 10.1126/science.1160809]

[29] Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 2016; 41(3): 211-8. [PMID: 26778478 DOI: 10.1016/j.tibs.2015.12.001]

[30] Fang C, Peng Q, Li X, Qu X, Qiao Z, et al. Multichannel immune nanoregulators suppress lactic acid metabolism and lactic acid-shaped acidic microenvironment to uproot anti-tumor immunosuppression. Adv Mater 2026; 38(3): e12230. [PMID: 41001978 DOI: 10.1002/adma.202512230]

[31] Liu Q, Chen X, Tan Y, Liu J, Zhu M, et al. Natural products as glycolytic inhibitors for cervical cancer treatment: a comprehensive review. Biomed Pharmacother 2024; 175: 116708. [PMID: 38723515 DOI: 10.1016/j.biopha.2024.116708]

[32] Nepstad I, Hatfield KJ, Grønningsæter IS, Reikvam H. The PI3K-Akt-mTOR signaling pathway in human acute myeloid leukemia (AML) cells. Int J Mol Sci 2020; 21(8): 2907. [PMID: 32326335 DOI: 10.3390/ijms21082907]

[33] Fontana F, Giannitti G, Marchesi S, Limonta P. The PI3K/Akt pathway and glucose metabolism: a dangerous liaison in cancer. Int J Biol Sci 2024; 20(8): 3113-25. [PMID: 38904014 DOI: 10.7150/ijbs.89942]

[34] Ma Z, Ding Y, Ding X, Mou H, Mo R, et al. PDK4 rescues high-glucose-induced senescent fibroblasts and promotes diabetic wound healing through enhancing glycolysis and regulating YAP and JNK pathway. Cell Death Discov 2023; 9(1): 424. [PMID: 38001078 DOI: 10.1038/s41420-023-01725-2]

[35] Brooks GA. The science and translation of lactate shuttle theory. Cell Metab 2018; 27(4): 757-85. [PMID: 29617642 DOI: 10.1016/j.cmet.2018.03.008]

[36] Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 2004; 558(Pt 1): 5-30. [PMID: 15131240 DOI: 10.1113/jphysiol.2003.058701]

[37] Soeters PB, Shenkin A, Sobotka L, Soeters MR, de Leeuw PW, et al. The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease. Clin Nutr 2021; 40(5): 2988-98. [PMID: 33674148 DOI: 10.1016/j.clnu.2021.02.012]

[38] Mao Y, Zhang J, Zhou Q, He X, Zheng Z, et al. Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation. Cell Res 2024; 34(1): 13-30. [PMID: 38163844 DOI: 10.1038/s41422-023-00864-6]

[39] Gaffney DO, Jennings EQ, Anderson CC, Marentette JO, Shi T, et al. Non-enzymatic lysine lactoylation of glycolytic enzymes. Cell Chem Biol 2020; 27(2): 206-13.e6. [PMID: 31767537 DOI: 10.1016/j.chembiol.2019.11.005]

[40] Gonzatti MB, Hintzen JCJ, Sharma I, Najar MA, Tsusaka T, et al. Class I histone deacetylases catalyze lysine lactylation. J Biol Chem 2025; 301(10): 110602. [PMID: 40835008 DOI: 10.1016/j.jbc.2025.110602]

[41] Sun Y, Wang H, Cui Z, Yu T, Song Y, et al. Lactylation in cancer progression and drug resistance. Drug Resist Updat 2025; 81: 101248. [PMID: 40287994 DOI: 10.1016/j.drup.2025.101248]

[42] Brooks GA. The tortuous path of lactate shuttle discovery: from cinders and boards to the lab and ICU. J Sport Health Sci 2020; 9(5): 446-60. [PMID: 32444344 DOI: 10.1016/j.jshs.2020.02.006]

[43] Wang X, Liu H, Ni Y, Shen P, Han X. Lactate shuttle: from substance exchange to regulatory mechanism. Hum Cell 2022; 35(1): 1-14. [PMID: 34606041 DOI: 10.1007/s13577-021-00622-z]

[44] Brooks GA, Curl CC, Leija RG, Osmond AD, Duong JJ, et al. Tracing the lactate shuttle to the mitochondrial reticulum. Exp Mol Med 2022; 54(9): 1332-47. [PMID: 36075947 DOI: 10.1038/s12276-022-00802-3]

[45] Natsubori A, Hirai S, Kwon S, Ono D, Deng F, et al. Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle. iScience 2023; 26(1): 105830. [PMID: 36713262 DOI: 10.1016/j.isci.2022.105830]

[46] Wei T, Guo Y, Huang C, Sun M, Zhou B, et al. Fibroblast-to-cardiomyocyte lactate shuttle modulates hypertensive cardiac remodelling. Cell Biosci 2023; 13(1): 151. [PMID: 37580825 DOI: 10.1186/s13578-023-01098-0]

[47] Chen L, Lin Y, Zhu X, Zhuo S, Li Z, et al. MCT1-mediated lactate shuttle to mitochondria governs macrophage polarization and modulates glucose homeostasis by affecting β cells. Adv Sci (Weinh) 2025; 12(38): e14760. [PMID: 40660708 DOI: 10.1002/advs.202414760]

[48] D’Aria S, Maquet C, Li S, Dhup S, Lepez A, et al. Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8⁺ T cell memory development. Proc Natl Acad Sci U S A 2024; 121(13): e2306763121. [PMID: 38498711 DOI: 10.1073/pnas.2306763121]

[49] Menig-Benzig LS, Stühler V, Mazzola P, Heinrich H, Hofmann U, et al. Drug targeting of the monocarboxylate transporter MCT4 is a novel treatment strategy for metastatic ccRCC. Pharmacol Res 2025; 222: 108057. [PMID: 41349849 DOI: 10.1016/j.phrs.2025.108057]

[50] Fang Y, Liu W, Tang Z, Ji X, Zhou Y, et al. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology 2023; 77(1): 109-23. [PMID: 35043976 DOI: 10.1002/hep.32348]

[51] Ma M, Liu T, Chen H, Wang Z, Zhou J, et al. Monocarboxylate transporter 4 inhibition reduces synovial hyperproliferation and metabolic reprogramming under hypoxia in rheumatoid arthritis. Arch Med Res 2025; 57(1): 103283. [PMID: 40829205 DOI: 10.1016/j.arcmed.2025.103283]

[52] Jha MK, Passero JV, Rawat A, Ament XH, Yang F, et al. Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice. J Clin Invest 2021; 131(21): e141964. [PMID: 34491913 DOI: 10.1172/JCI141964]

[53] Ahmed K, Tunaru S, Tang C, Müller M, Gille A, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 2010; 11(4): 311-9. [PMID: 20374963 DOI: 10.1016/j.cmet.2010.02.012]

[54] Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 1994; 91(22): 10625-9. [PMID: 7938003 DOI: 10.1073/pnas.91.22.10625]

[55] Liu C, Wu J, Zhu J, Kuei C, Yu J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 2009; 284(5): 2811-22. [PMID: 19047060 DOI: 10.1074/jbc.M806409200]

[56] Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214(2): 199-210. [PMID: 18161745 DOI: 10.1002/path.2277]

[57] Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007; 127(3): 526-37. [PMID: 17299435 DOI: 10.1038/sj.jid.5700613]

[58] Wang LJ, Guo PF, Chen YZ, Yan HW, Zhang XL. Tangeretin in the treatment of pulmonary fibrosis: current advances and future perspectives. Curr Mol Pharmacol 2024; 17: e18761429385520. [PMID: 40370245 DOI: 10.2174/0118761429385520250508041438]

[59] Distler JHW, Györfi AH, Ramanujam M, Whitfield ML, Königshoff M, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019; 15(12): 705-30. [PMID: 31712723 DOI: 10.1038/s41584-019-0322-7]

[60] Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer 2022; 21(1): 104. [PMID: 35461253 DOI: 10.1186/s12943-022-01569-x]

[61] Bernard K, Logsdon NJ, Ravi S, Xie N, Persons BP, et al. Metabolic reprogramming is required for myofibroblast contractility and differentiation. J Biol Chem 2015; 290(42): 25427-38. [PMID: 26318453 DOI: 10.1074/jbc.M115.646984]

[62] Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007; 117(12): 3810-20. [PMID: 18037992 DOI: 10.1172/JCI30487]

[63] Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377(9779): 1760-9. [PMID: 21571362 DOI: 10.1016/S0140-6736(11)60405-4]

[64] Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370(22): 2071-82. [PMID: 24836310 DOI: 10.1056/NEJMoa1402584]

[65] Shen Y, Li X, Wei D, Guo H, Yang X, et al. Synergistic effects of diammonium glycyrrhizinate and vitamin D3 against EMT in pulmonary fibrosis through modulating the crosstalk of STAT3/HSP90AA1 and HIF-1α pathway. J Ethnopharmacol 2026; 359: 120649. [PMID: 41423159 DOI: 10.1016/j.jep.2025.120649]

[66] Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother 2021; 135: 111067. [PMID: 33383375 DOI: 10.1016/j.biopha.2020.111067]

[67] Newton DA, Lottes RG, Ryan RM, Spyropoulos DD, Baatz JE. Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue. Respir Res 2021; 22(1): 278. [PMID: 34711218 DOI: 10.1186/s12931-021-01866-x]

[68] Parimon T, Yao C, Stripp BR, Noble PW, Chen P. Alveolar epithelial type II cells as drivers of lung fibrosis in idiopathic pulmonary fibrosis. Int J Mol Sci 2020; 21(7): 2269. [PMID: 32218238 DOI: 10.3390/ijms21072269]

[69] Feng J, Zhong H, Mei S, Tang R, Zhou Y, et al. LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis. Cell Mol Life Sci 2024; 81(1): 206. [PMID: 38709307 DOI: 10.1007/s00018-024-05242-y]

[70] Sun Z, He W, Meng H, Ji Z, Qu J, et al. Lactate activates ER stress to promote alveolar epithelial cells apoptosis in pulmonary fibrosis. Respir Res 2024; 25(1): 401. [PMID: 39522031 DOI: 10.1186/s12931-024-03016-5]

[71] Wang P, Xie D, Xiao T, Cheng C, Wang D, et al. H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP. J Hazard Mater 2024; 461: 132582. [PMID: 37742376 DOI: 10.1016/j.jhazmat.2023.132582]

[72] Liu S, He Y, Jin L, Shi S, Zhang J, et al. H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells. Toxicology 2025; 514: 154109. [PMID: 40049282 DOI: 10.1016/j.tox.2025.154109]

[73] Wei Y, Guo H, Chen S, Tang XX. Regulation of macrophage activation by lactylation in lung disease. Front Immunol 2024; 15: 1427739. [PMID: 39026681 DOI: 10.3389/fimmu.2024.1427739]

[74] Yan P, Yang K, Xu M, Zhu M, Duan Y, et al. CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production. J Mol Cell Biol 2024; 16(5): mjae021. [PMID: 38760881 DOI: 10.1093/jmcb/mjae021]

[75] Wang L, Yuan H, Li W, Yan P, Zhao M, et al. ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870(2): 166960. [PMID: 37979225 DOI: 10.1016/j.bbadis.2023.166960]

[76] Callaghan NI, Davenport Huyer L. Altered metabolism in idiopathic pulmonary fibrosis. J Cell Physiol 2025; 240(12): e70112. [PMID: 41424408 DOI: 10.1002/jcp.70112]

[77] Gao H, Sun Z, Hu X, Song W, Liu Y, et al. Identification of glycolysis-related gene signatures for prognosis and therapeutic targeting in idiopathic pulmonary fibrosis. Front Pharmacol 2025; 16: 1486357. [PMID: 40093327 DOI: 10.3389/fphar.2025.1486357]

[78] Gui X, Qiu X, Tian Y, Xie M, Li H, et al. Prognostic value of IFN-γ, sCD163, CCL2 and CXCL10 involved in acute exacerbation of idiopathic pulmonary fibrosis. Int Immunopharmacol 2019; 70: 208-15. [PMID: 30851700 DOI: 10.1016/j.intimp.2019.02.039]

[79] Liu Z, Liu W, Wei H, Ping Y, Yu Z, et al. Elevated lactate production exacerbates PM2.5-induced pulmonary fibrosis by stabilizing TGF-β1. J Adv Res 2026; 83: 299-314. [PMID: 40759348 DOI: 10.1016/j.jare.2025.07.057]

[80] Xie N, Cui H, Ge J, Banerjee S, Guo S, et al. Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2017; 313(5): L834-44. [PMID: 28798256 DOI: 10.1152/ajplung.00235.2017]

[81] Xu Q, Mei S, Nie F, Zhang Z, Feng J, et al. The role of macrophage-fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis. Lab Invest 2022; 102(4): 432-9. [PMID: 34775492 DOI: 10.1038/s41374-021-00701-7]

[82] Cui H, Xie N, Banerjee S, Ge J, Jiang D, et al. Lung myofibroblasts promote macrophage profibrotic activity through lactate-induced histone lactylation. Am J Respir Cell Mol Biol 2021; 64(1): 115-25. [PMID: 33074715 DOI: 10.1165/rcmb.2020-0360OC]

[83] Shi L, Zhang L, Ma Z, Hu Z, Geng Z, et al. H3K18 lactylation drives the progression of silica nanoparticles-induced pulmonary fibrosis via promoting macrophage M1 polarization. J Hazard Mater 2025; 496: 139286. [PMID: 40690843 DOI: 10.1016/j.jhazmat.2025.139286]

[84] Wang H, Gao Y, Wang L, Yu Y, Zhang J, et al. Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program. J Adv Res 2023; 44: 213-25. [PMID: 36725191 DOI: 10.1016/j.jare.2022.04.012]

[85] Shinoda H, Tasaka S, Fujishima S, Yamasawa W, Miyamoto K, et al. Elevated CC chemokine level in bronchoalveolar lavage fluid is predictive of a poor outcome of idiopathic pulmonary fibrosis. Respiration 2009; 78(3): 285-92. [PMID: 19270434 DOI: 10.1159/000207617]

[86] Hu Y, Yang L, Huang L, Zeng C, Ren S. m6A reader IGF2BP1 facilitates macrophage glycolytic metabolism and fibrotic phenotype by stabilizing THBS1 mRNA to promote pulmonary fibrosis. Cell Mol Life Sci 2025; 82(1): 157. [PMID: 40220148 DOI: 10.1007/s00018-025-05673-1]

[87] Liu C, Zhang Q, Zhou H, Jin L, Liu C, et al. GLP-1R activation attenuates the progression of pulmonary fibrosis via disrupting NLRP3 inflammasome/PFKFB3-driven glycolysis interaction and histone lactylation. J Transl Med 2024; 22(1): 954. [PMID: 39434134 DOI: 10.1186/s12967-024-05753-z]

[88] Zhao G, Zhou J, He S, Fei X, Guo G. The role of lactylation in virus-host interactions. Int J Mol Sci 2025; 26(14): 6613. [PMID: 40724863 DOI: 10.3390/ijms26146613]

[89] Rho H, Hay N. Protein lactylation in cancer: mechanisms and potential therapeutic implications. Exp Mol Med 2025; 57(3): 545-53. [PMID: 40128358 DOI: 10.1038/s12276-025-01410-7]

[90] Shi P, Ma Y, Zhang S. Non-histone lactylation: unveiling its functional significance. Front Cell Dev Biol 2025; 13: 1535611. [PMID: 39925738 DOI: 10.3389/fcell.2025.1535611]

[91] Deng YT, Ma L, Mei Y, Wang JS, Bai XH, et al. Amphiregulin contributes to neuropathic pain by enhancing glycolysis that stimulates histone lactylation in sensory neurons. Sci Signal 2025; 18(891): eadr9397. [PMID: 40526786 DOI: 10.1126/scisignal.adr9397]

[92] Liu J, Zhao L, Yan M, Jin S, Shang L, et al. H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer. J Exp Clin Cancer Res 2025; 44(1): 252. [PMID: 40849487 DOI: 10.1186/s13046-025-03512-6]

[93] Zhu R, Ye X, Lu X, Xiao L, Yuan M, et al. ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion. Cell Metab 2025; 37(2): 361-76.e7. [PMID: 39561764 DOI: 10.1016/j.cmet.2024.10.015]

[94] Chen J, He J, Wang X, Bai L, Yang X, et al. Glis1 inhibits RTEC cellular senescence and renal fibrosis by downregulating histone lactylation in DKD. Life Sci 2025; 361: 123293. [PMID: 39643036 DOI: 10.1016/j.lfs.2024.123293]

[95] Xie B, Zhang M, Li J, Cui J, Zhang P, et al. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. Proc Natl Acad Sci U S A 2024; 121(8): e2314128121. [PMID: 38359291 DOI: 10.1073/pnas.2314128121]

[96] Niu Z, Chen C, Wang S, Lu C, Wu Z, et al. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun 2024; 15(1): 3561. [PMID: 38670996 DOI: 10.1038/s41467-024-47900-6]

[97] Yin D, Jiang N, Cheng C, Sang X, Feng Y, et al. Protein lactylation and metabolic regulation of the zoonotic parasite Toxoplasma gondii. Genomics Proteomics Bioinformatics 2023; 21(6): 1163-81. [PMID: 36216028 DOI: 10.1016/j.gpb.2022.09.010]

[98] Sun S, Xu Z, He L, Shen Y, Yan Y, et al. Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation. Nat Commun 2024; 15(1): 8377. [PMID: 39333081 DOI: 10.1038/s41467-024-52729-0]

[99] Wang J, Wang Z, Wang Q, Li X, Guo Y. Ubiquitous protein lactylation in health and diseases. Cell Mol Biol Lett 2024; 29(1): 23. [PMID: 38317138 DOI: 10.1186/s11658-024-00541-5]

[100] Wang Z, Liu Z, Lv M, Luan Z, Li T, et al. Novel histone modifications and liver cancer: emerging frontiers in epigenetic regulation. Clin Epigenetics 2025; 17(1): 30. [PMID: 39980025 DOI: 10.1186/s13148-025-01838-8]

[101] Ma C, Liao R, Chen X, Cao Q, Deng X, et al. RHOA lactylation at oncogenic hotspots promotes oncogenic activity and protein stabilization. Mol Cancer 2025; 24(1): 311. [PMID: 41291745 DOI: 10.1186/s12943-025-02511-7]

[102] Zhang TN, Huang XM, Li L, Li Y, Liu YP, et al. Lactylation of HADHA promotes sepsis-induced myocardial depression. Circ Res 2025; 137(4): e65-87. [PMID: 40575877 DOI: 10.1161/CIRCRESAHA.124.325708]

[103] Zhang X, Liu Y, Rekowski MJ, Wang N. Lactylation of tau in human Alzheimer’s disease brains. Alzheimers Dement 2025; 21(2): e14481. [PMID: 39740133 DOI: 10.1002/alz.14481]

[104] Wang Y, Li H, Jiang S, Fu D, Lu X, et al. The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation. Kidney Int 2024; 106(2): 226-40. [PMID: 38789037 DOI: 10.1016/j.kint.2024.04.016]

[105] Zhang C, Zhou T, Li C, Wang D, Tao J, et al. Deciphering novel enzymatic and non-enzymatic lysine lactylation in Salmonella. Emerg Microbes Infect 2025; 14(1): 2475838. [PMID: 40035788 DOI: 10.1080/22221751.2025.2475838]

[106] Trujillo MN, Jennings EQ, Hoffman EA, Zhang H, Phoebe AM, et al. Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation. Mol Metab 2024; 81: 101888. [PMID: 38307385 DOI: 10.1016/j.molmet.2024.101888]

[107] Clément C, Dorion S, Bykova NV, Fetterley V, Branchini E, et al. Implication of S-d-lactoylglutathione in the spontaneous cysteine S-glutathionylation and lysine N-lactoylation of Arabidopsis thaliana NAD-dependent glyceraldehyde-3-phosphate dehydrogenase. Int J Mol Sci 2025; 26(19): 9673. [PMID: 41096938 DOI: 10.3390/ijms26199673]

[108] Moreno-Yruela C, Bæk M, Monda F, Olsen CA . Chiral post-translational modification to lysine ε-amino groups. Acc Chem Res 2022; 55(10): 1456-66. [PMID: 35500056 DOI: 10.1021/acs.accounts.2c00115]

[109] Li F, Si W, Xia L, Yin D, Wei T, et al. Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Mol Cancer 2024; 23(1): 90. [PMID: 38711083 DOI: 10.1186/s12943-024-02008-9]

[110] Lv J, Yu X, Liu X, Zhang Q, Zhang M, et al. The LncRNA STEAP3-AS1 promotes liver metastasis in colorectal cancer by regulating histone lactylation through chromatin remodelling. J Exp Clin Cancer Res 2025; 44(1): 205. [PMID: 40665344 DOI: 10.1186/s13046-025-03461-0]

[111] Chen H, Li Y, Li H, Chen X, Fu H, et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature 2024; 631(8021): 663-9. [PMID: 38961290 DOI: 10.1038/s41586-024-07620-9]

[112] Lin J, Yin Y, Cao J, Zhang Y, Chen J, et al. NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance. Cell Discov 2025; 11(1): 52. [PMID: 40425546 DOI: 10.1038/s41421-025-00804-1]

[113] Moreno-Yruela C, Zhang D, Wei W, Bæk M, Liu W, et al. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv 2022; 8(3): eabi6696. [PMID: 35044827 DOI: 10.1126/sciadv.abi6696]

[114] Fan Z, Liu Z, Zhang N, Wei W, Cheng K, et al. Identification of SIRT3 as an eraser of H4K16la. iScience 2023; 26(10): 107757. [PMID: 37720100 DOI: 10.1016/j.isci.2023.107757]

[115] Fan W, Zeng S, Wang X, Wang G, Liao D, et al. A feedback loop driven by H3K9 lactylation and HDAC2 in endothelial cells regulates VEGF-induced angiogenesis. Genome Biol 2024; 25(1): 165. [PMID: 38918851 DOI: 10.1186/s13059-024-03308-5]

[116] Zou Y, Cao M, Tai M, Zhou H, Tao L, et al. A feedback loop driven by H4K12 lactylation and HDAC3 in macrophages regulates lactate-induced collagen synthesis in fibroblasts via the TGF-β signaling. Adv Sci (Weinh) 2025; 12(13): e2411408. [PMID: 39945346 DOI: 10.1002/advs.202411408]

[117] Zhou J, Qiu S, Yang X, Wu Y, Yao X, et al. Hypoxia-induced PRMT1 lactylation drives vimentin arginine asymmetric dimethylation in tumor metastasis. Adv Sci (Weinh) 2025; 12(41): e09861. [PMID: 40884268 DOI: 10.1002/advs.202509861]

[118] Tsukihara S, Akiyama Y, Shimada S, Hatano M, Igarashi Y, et al. Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. Oncogene 2025; 44(11): 724-38. [PMID: 39658647 DOI: 10.1038/s41388-024-03243-6]

[119] Sun Y, Chen Y, Xu Y, Zhang Y, Lu M, et al. Genetic encoding of ε- N-l-lactyllysine for detecting delactylase activity in living cells. Chem Commun (Camb) 2022; 58(61): 8544-7. [PMID: 35815577 DOI: 10.1039/d2cc02643k]

[120] Zhang N, Zhang Y, Xu J, Wang P, Wu B, et al. α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure. Cell Res 2023; 33(9): 679-98. [PMID: 37443257 DOI: 10.1038/s41422-023-00844-w]

[121] Chen C, Zhang Y, Zang Y, Fan Z, Han Y, et al. SIRT3 functions as an eraser of histone H3K9 lactylation to modulate transcription for inhibiting the progression of esophageal cancer. Mol Cell Proteomics 2025; 24(5): 100973. [PMID: 40252727 DOI: 10.1016/j.mcpro.2025.100973]

[122] Wang ZA, Markert J, Whedon SD, Abeywardana MY, Sheng X, et al. Structural and enzymatic plasticity of SIRT6 deacylase activity. J Biol Chem 2025; 301(5): 108446. [PMID: 40147774 DOI: 10.1016/j.jbc.2025.108446]

[123] Hu X, Huang X, Yang Y, Sun Y, Zhao Y, et al. Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader. Nucleic Acids Res 2024; 52(10): 5529-48. [PMID: 38512058 DOI: 10.1093/nar/gkae183]

[124] Zhai G, Niu Z, Jiang Z, Zhao F, Wang S, et al. DPF2 reads histone lactylation to drive transcription and tumorigenesis. Proc Natl Acad Sci U S A 2024; 121(50): e2421496121. [PMID: 39636855 DOI: 10.1073/pnas.2421496121]

[125] Nuñez R, Sidlowski PFW, Steen EA, Wynia-Smith SL, Sprague DJ, et al. The TRIM33 bromodomain recognizes histone lysine lactylation. ACS Chem Biol 2024; 19(12): 2418-28. [PMID: 39556662 DOI: 10.1021/acschembio.4c00248]

[126] Dai C, Tang Y, Yang H, Zheng J. YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression. Mol Cell 2025; 85(14): 2733-48.e7. [PMID: 40680722 DOI: 10.1016/j.molcel.2025.06.017]

[127] Iozzo M, Pardella E, Giannoni E, Chiarugi P. The role of protein lactylation: a kaleidoscopic post-translational modification in cancer. Mol Cell 2025; 85(7): 1263-79. [PMID: 40073861 DOI: 10.1016/j.molcel.2025.02.011]

[128] Yu X, Yang J, Xu J, Pan H, Wang W, et al. Histone lactylation: from tumor lactate metabolism to epigenetic regulation. Int J Biol Sci 2024; 20(5): 1833-54. [PMID: 38481814 DOI: 10.7150/ijbs.91492]

[129] Liu R, Ren X, Park YE, Feng H, Sheng X, et al. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis. Cell Metab 2025; 37(2): 377-94.e9. [PMID: 39642882 DOI: 10.1016/j.cmet.2024.11.005]

[130] Sui Y, Shen Z, Wang Z, Feng J, Zhou G. Lactylation in cancer: metabolic mechanism and therapeutic strategies. Cell Death Discov 2025; 11(1): 68. [PMID: 39979245 DOI: 10.1038/s41420-025-02349-4]

[131] Ziogas A, Novakovic B, Ventriglia L, Galang N, Tran KA, et al. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory. Cell 2025; 188(11): 2992-3012.e16. [PMID: 40318634 DOI: 10.1016/j.cell.2025.03.048]

[132] Raychaudhuri D, Singh P, Chakraborty B, Hennessey M, Tannir AJ, et al. Histone lactylation drives CD8⁺ T cell metabolism and function. Nat Immunol 2024; 25(11): 2140-51. [PMID: 39375549 DOI: 10.1038/s41590-024-01985-9]

[133] Yang J, Yu X, Xiao M, Xu H, Tan Z, et al. Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer. Gut 2025; 74(11): 1859-72. [PMID: 40467104 DOI: 10.1136/gutjnl-2024-334361]

[134] Wang S, Huang T, Wu Q, Yuan H, Wu X, et al. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation. J Clin Invest 2024; 134(22): e176851. [PMID: 39545414 DOI: 10.1172/jci176851]

[135] Lv M, Yang X, Xu C, Song Q, Zhao H, et al. SIRT4 promotes pancreatic cancer stemness by enhancing histone lactylation and epigenetic reprogramming stimulated by calcium signaling. Adv Sci (Weinh) 2025; 12(20): e2412553. [PMID: 40298941 DOI: 10.1002/advs.202412553]

[136] Huang Y, Wang C, Zhou T, Xie F, Liu Z, et al. Lumican promotes calcific aortic valve disease through H3 histone lactylation. Eur Heart J 2024; 45(37): 3871-85. [PMID: 38976370 DOI: 10.1093/eurheartj/ehae407]

[137] Zhang Y, Song H, Li M, Lu P. Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: oncometabolite fuels oncogenic transcription. Clin Transl Med 2024; 14(3): e1614. [PMID: 38456209 DOI: 10.1002/ctm2.1614]

[138] Wang N, Wang W, Wang X, Mang G, Chen J, et al. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ Res 2022; 131(11): 893-908. [PMID: 36268709 DOI: 10.1161/CIRCRESAHA.122.320488]

[139] Zhang J, Wu D, Zeng F, Gu H, Li C, et al. Lactate metabolic reprogramming and histone lactylation modification in sepsis. Int J Biol Sci 2025; 21(11): 5034-55. [PMID: 40860191 DOI: 10.7150/ijbs.116088]

[140] Zhang Q, Han Z, Liu JH, Li M, Li W, et al. Hypoxia facilitates stemness of colon cancer cells via histone lactylation. Biochim Biophys Acta Mol Basis Dis 2025; 1871(8): 167993. [PMID: 40716503 DOI: 10.1016/j.bbadis.2025.167993]

[141] Zhao SS, Liu J, Wu QC, Zhou XL. Lactate regulates pathological cardiac hypertrophy via histone lactylation modification. J Cell Mol Med 2024; 28(16): e70022. [PMID: 39205384 DOI: 10.1111/jcmm.70022]

[142] Chen A, Chen Z, Huang B, Lian G, Luo L, et al. Hypoxia-induced histone lactylation promotes pulmonary arterial smooth muscle cells proliferation in pulmonary hypertension. Mol Cell Biochem 2025; 480(11): 5685-97. [PMID: 40588665 DOI: 10.1007/s11010-025-05342-8]

[143] Zhang YM, Yang F, Li Q, Zhang JN. Role of histone lactylation in neurological disorders. Int J Mol Sci 2025; 26(16): 7949. [PMID: 40869269 DOI: 10.3390/ijms26167949]

[144] Liang Z, Liu J, Gou Y, Wang H, Li Z, et al. Elevated histone lactylation mediates ferroptosis resistance in endometriosis through the METTL3-regulated HIF1A/HMOX1 signaling pathway. Adv Sci (Weinh) 2025; 12(31): e08220. [PMID: 40492577 DOI: 10.1002/advs.202408220]

[145] Liu Y, Guo X, Hu X, Zhou S, Yang Q, et al. Lysine lactylation in diseases: beyond histone lactylation. Cell Death Dis 2025; 17(1): 55. [PMID: 41285721 DOI: 10.1038/s41419-025-08223-6]

[146] Zhang Q, Luo B, Sun X, Nagashima H, Wu Y, et al. Non-histone lysine lactylation: emerging roles in tumor biology and therapeutic implications. Ageing Res Rev 2025; 112: 102875. [PMID: 40825375 DOI: 10.1016/j.arr.2025.102875]

[147] Kim JY, Sim H, Na AY, Choi SY, Lee S. Global profiling of lysine lactylation in prostate cancer cells. Cancer Genomics Proteomics 2025; 22(6): 929-39. [PMID: 41151862 DOI: 10.21873/cgp.20547]

[148] Yang YH, Wang QC, Kong J, Yang JT, Liu JF. Global profiling of lysine lactylation in human lungs. Proteomics 2023; 23(15): e2200437. [PMID: 37170646 DOI: 10.1002/pmic.202200437]

[149] Dong H, Zhang J, Zhang H, Han Y, Lu C, et al. YiaC and CobB regulate lysine lactylation in Escherichia Coli. Nat Commun 2022; 13(1): 6628. [PMID: 36333310 DOI: 10.1038/s41467-022-34399-y]

[150] Peng X, Du J. Histone and non-histone lactylation: molecular mechanisms, biological functions, diseases, and therapeutic targets. Mol Biomed 2025; 6(1): 38. [PMID: 40484921 DOI: 10.1186/s43556-025-00275-6]

[151] Li S, Dong L, Wang K. Current and future perspectives of lysine lactylation in cancer. Trends Cell Biol 2025; 35(3): 190- 3. [PMID: 39837737 DOI: 10.1016/j.tcb.2024.12.015]

[152] Yang Z, Zheng Y, Gao Q. Lysine lactylation in the regulation of tumor biology. Trends Endocrinol Metab 2024; 35(8): 720-31. [PMID: 38395657 DOI: 10.1016/j.tem.2024.01.011]

[153] Gao X, Pang C, Fan Z, Wang Y, Duan Y, et al. Regulation of newly identified lysine lactylation in cancer. Cancer Lett 2024; 587: 216680. [PMID: 38346584 DOI: 10.1016/j.canlet.2024.216680]

[154] Chen J, Feng Q, Qiao Y, Pan S, Liang L, et al. ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes. Diabetologia 2024; 67(7): 1429-43. [PMID: 38676722 DOI: 10.1007/s00125-024-06156-x]

[155] Fan M, Yang K, Wang X, Chen L, Gill PS, et al. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction. Sci Adv 2023; 9(5): eadc9465. [PMID: 36735787 DOI: 10.1126/sciadv.adc9465]

[156] Pan RY, He L, Zhang J, Liu X, Liao Y, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab 2022; 34(4): 634-48.e6. [PMID: 35303422 DOI: 10.1016/j.cmet.2022.02.013]

[157] Llibre A, Kucuk S, Gope A, Certo M, Mauro C. Lactate: a key regulator of the immune response. Immunity 2025; 58(3): 535-54. [PMID: 40073846 DOI: 10.1016/j.immuni.2025.02.008]

[158] Yang Y, Deng L, Zhang H, Hu J, Li J, et al. Function and mechanism of lactylation in health and diseases: a comprehensive review. Int J Surg 2025; 111(8): 5387-402. [PMID: 40511917 DOI: 10.1097/js9.0000000000002623]

[159] Susser LI, Nguyen MA, Geoffrion M, Emerton C, Ouimet M, et al. Mitochondrial fragmentation promotes inflammation resolution responses in macrophages via histone lactylation. Mol Cell Biol 2023; 43(10): 531-46. [PMID: 37807652 DOI: 10.1080/10985549.2023.2253131]

[160] You X, Xie Y, Tan Q, Zhou C, Gu P, et al. Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification. Ecotoxicol Environ Saf 2024; 283: 116952. [PMID: 39217895 DOI: 10.1016/j.ecoenv.2024.116952]

[161] Zou W, Zhang Z, Cao T, Li M. Mesenchymal stem cell transplantation ameliorates inflammation in spinal cord injury by inhibiting lactylation-related genes. Cytokine 2025; 191: 156960. [PMID: 40345018 DOI: 10.1016/j.cyto.2025.156960]

[162] Al-Malsi K, Xie S, Cai Y, Mohammed N, Xie K, et al. The role of lactylation in tumor growth and cancer progression. Front Oncol 2025; 15: 1516785. [PMID: 39968078 DOI: 10.3389/fonc.2025.1516785]

[163] Li W, Zhou J, Gu Y, Chen Y, Huang Y, et al. Lactylation of RNA m⁶A demethylase ALKBH5 promotes innate immune response to DNA herpesviruses and mpox virus. Proc Natl Acad Sci U S A 2024; 121(43): e2409132121. [PMID: 39413129 DOI: 10.1073/pnas.2409132121]

[164] Wang X, Yan X, Mang G, Chen Y, Liu S, et al. S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury. J Clin Invest 2025; 135(24): e194664. [PMID: 41066195 DOI: 10.1172/jci194664]

[165] Wu X, Liu C, Zhang C, Kuai L, Hu S, et al. The role of lactate and lactylation in the dysregulation of immune responses in psoriasis. Clin Rev Allergy Immunol 2025; 68(1): 28. [PMID: 40080284 DOI: 10.1007/s12016-025-09037-2]

[166] Ma Y, Zhang Z, Cao X, Guo D, Huang S, et al. Semaphorin 6A phase separation sustains a histone lactylation-dependent lactate buildup in pathological angiogenesis. Proc Natl Acad Sci U S A 2025; 122(16): e2423677122. [PMID: 40244673 DOI: 10.1073/pnas.2423677122]

[167] Wang X, Huang J, Fan W, Li N, Yang H, et al. Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation. Genome Biol 2025; 26(1): 377. [PMID: 41168862 DOI: 10.1186/s13059-025-03845-7]

[168] Zhao M, Qian Y, He L, Peng T, Wang H, et al. Lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis. Cell Death Dis 2025; 16(1): 701. [PMID: 41053006 DOI: 10.1038/s41419-025-08023-y]

[169] Zuo S, Li L, Tang J, Ye F, Sok, et al. Lactylation-boosted m⁵C RNA modification drives choroidal neovascularization. Research (Wash D C) 2025; 8: 0913. [PMID: 41049616 DOI: 10.34133/research.0913]

[170] Shen W, Nie Z, Wang M, Zhang H, Liu Y, et al. Monocyte-derived exosomal periostin driven by histone lactylation contributes to retinal neovascularization. Proc Natl Acad Sci U S A 2025; 122(44): e2501704122. [PMID: 41150725 DOI: 10.1073/pnas.2501704122]

[171] Wang X, Fan W, Li N, Ma Y, Yao M, et al. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2. Genome Biol 2023; 24(1): 87. [PMID: 37085894 DOI: 10.1186/s13059-023-02931-y]

[172] Yu Z, Zhou X, Wang X. Metabolic reprogramming in hematologic malignancies: advances and clinical perspectives. Cancer Res 2022; 82(17): 2955-63. [PMID: 35771627 DOI: 10.1158/0008-5472.CAN-22-0917]

[173] Perez LM, Venugopal SV, Martin AS, Freedland SJ, Di Vizio D, et al. Mechanisms governing lineage plasticity and metabolic reprogramming in cancer. Trends Cancer 2024; 10(11): 1009-22. [PMID: 39218770 DOI: 10.1016/j.trecan.2024.08.001]

[174] Yang Y, Wu Y, Chen H, Xu Z, Lu R, et al. Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors. Front Immunol 2025; 16: 1595162. [PMID: 40755753 DOI: 10.3389/fimmu.2025.1595162]

[175] Wang T, Ye Z, Li Z, Jing DS, Fan GX, et al. Lactate-induced protein lactylation: a bridge between epigenetics and metabolic reprogramming in cancer. Cell Prolif 2023; 56(10): e13478. [PMID: 37060186 DOI: 10.1111/cpr.13478]

[176] Zhang D, Liang C, Wu C, Hawanga M, Wan S, et al. Nonhistone lactylation: a hub for tumour metabolic reprogramming and epigenetic regulation. J Transl Med 2025; 23(1): 901. [PMID: 40797262 DOI: 10.1186/s12967-025-06813-8]

[177] Ge X, Zhu Y, Xiong J, Gu Y, Wang X, et al. Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8⁺ T lymphocytes and aggravates spinal cord injury. Neuron 2025; 113(14): 2280-96.e8. [PMID: 40328251 DOI: 10.1016/j.neuron.2025.04.003]

[178] Chen L, Huang L, Gu Y, Cang W, Sun P, et al. Lactate-lactylation hands between metabolic reprogramming and immunosuppression. Int J Mol Sci 2022; 23(19): 11943. [PMID: 36233246 DOI: 10.3390/ijms231911943]

[179] Chen S, Qin T, Luo S, Wang F, Chen F, et al. Lactylation and viral infections: a novel link between metabolic reprogramming and immune regulation. PLoS Pathog 2025; 21(7): e1013366. [PMID: 40720394 DOI: 10.1371/journal.ppat.1013366]

[180] She H, Hu Y, Zhao G, Du Y, Wu Y, et al. Dexmedetomidine ameliorates myocardial ischemia-reperfusion injury by inhibiting MDH2 lactylation via regulating metabolic reprogramming. Adv Sci (Weinh) 2024; 11(48): e2409499. [PMID: 39467114 DOI: 10.1002/advs.202409499]

[181] Jia M, Yue X, Sun W, Zhou Q, Chang C, et al. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv 2023; 9(22): eadg4993. [PMID: 37267363 DOI: 10.1126/sciadv.adg4993]

[182] Zheng J, She H, Han R, Tang J, Dou Y, et al. Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis. Dev Cell 2025; 60(23): 3267-84.e7. [PMID: 40812308 DOI: 10.1016/j.devcel.2025.07.014]

[183] Yin YC, He J, Feng Y, Xu YY, Shi XH, et al. Filactate-induced lysine lactylation: a central node linking metabolic rewiring, epigenetic plasticity and therapeutic vulnerabilities in hepatocellular carcinoma. J Biochem Mol Toxicol 2025; 39(12): e70622. [PMID: 41293912 DOI: 10.1002/jbt.70622]

[184] Liu X, Zhang Y, Li W, Zhou X. Lactylation, an emerging hallmark of metabolic reprogramming: current progress and open challenges. Front Cell Dev Biol 2022; 10: 972020. [PMID: 36092712 DOI: 10.3389/fcell.2022.972020]

[185] Chen AN, Luo Y, Yang YH, Fu JT, Geng XM, et al. Lactylation, a novel metabolic reprogramming code: current status and prospects. Front Immunol 2021; 12: 688910. [PMID: 34177945 DOI: 10.3389/fimmu.2021.688910]

[186] Dong Q, Zhang Q, Yang X, Nai S, Du X, et al. Glycolysis-stimulated Esrrb lactylation promotes the self-renewal and extraembryonic endoderm stem cell differentiation of embryonic stem cells. Int J Mol Sci 2024; 25(5): 2692. [PMID: 38473939 DOI: 10.3390/ijms25052692]

[187] Ye Z, Chen X, Zou J, Wu W, Yang J, et al. Lactylation’s role in bone health and disease: mechanistic insights and therapeutic potential. PeerJ 2025; 13: e19534. [PMID: 40511385 DOI: 10.7717/peerj.19534]

[188] Chen Y, Wu J, Zhai L, Zhang T, Yin H, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell 2024; 187(2): 294-311.e21. [PMID: 38128537 DOI: 10.1016/j.cell.2023.11.022]

[189] Hagihara H, Shoji H, Otabi H, Toyoda A, Katoh K, et al. Protein lactylation induced by neural excitation. Cell Rep 2021; 37(2): 109820. [PMID: 34644564 DOI: 10.1016/j.celrep.2021.109820]

[190] Xu W, Zhao A, Han R, Wei J, Yu Q, et al. Extracellular lactate improves neurogenesis by modulating H3K9 lactylation and SnoN expression under hypoxic conditions. Stem Cell Res Ther 2025; 16(1): 462. [PMID: 40866997 DOI: 10.1186/s13287-025-04571-4]

[191] Wei L, Yang X, Wang J, Wang Z, Wang Q, et al. H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer’s disease through the NFκB signaling pathway. J Neuroinflammation 2023; 20(1): 208. [PMID: 37697347 DOI: 10.1186/s12974-023-02879-7]

[192] Zhou J, Zhang L, Peng J, Zhang X, Zhang F, et al. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab 2024; 36(9): 2054-68.e14. [PMID: 38906140 DOI: 10.1016/j.cmet.2024.05.016]

[193] Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017; 8: 14532. [PMID: 28230051 DOI: 10.1038/ncomms14532]

[194] Yanai H, Shteinberg A, Porat Z, Budovsky A, Braiman A, et al. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY) 2015; 7(9): 664-72. [PMID: 26399448 DOI: 10.18632/aging.100807]

[195] Sun Z, Ji Z, He W, Duan R, Qu J, et al. Lactate accumulation induced by Akt2-PDK1 signaling promotes pulmonary fibrosis. FASEB J 2024; 38(2): e23426. [PMID: 38226859 DOI: 10.1096/fj.202302063RR]

[196] Wu J, Li Y, Yang Y, Chen R, Wang H, et al. Wogonoside inhibits fibroblast activation and pulmonary fibrosis by dual regulation of Snail1 lactylation and PGC1α/PINK1-mediated mitophagy. Phytomedicine 2025; 147: 157240. [PMID: 40939548 DOI: 10.1016/j.phymed.2025.157240]

[197] Chen S, Wang Y, Zhang J, Liu B, Liu W, et al. YTHDC1 phase separation drives the nuclear export of m⁶A-modified lncNONMMUT062668.2 through the transport complex SRSF3-ALYREF-XPO5 to aggravate pulmonary fibrosis. Cell Death Dis 2025; 16(1): 279. [PMID: 40221424 DOI: 10.1038/s41419-025-07608-x]

[198] Wenhao L, Ling H, Wanqing F, Wanrong W, Chao C, et al. IGFBP7 and CCT2 are novel lactylation-driven mediators of endothelial-to-mesenchymal transition in idiopathic pulmonary fibrosis. Funct Integr Genomics 2025; 25(1): 250. [PMID: 41261179 DOI: 10.1007/s10142-025-01761-4]

[199] Xiong J, He J, Zhu J, Pan J, Liao W, et al. Lactylation-driven METTL3-mediated RNA m⁶A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell 2022; 82(9): 1660-77.e10. [PMID: 35320754 DOI: 10.1016/j.molcel.2022.02.033]

[200] Wu D, Spencer CB, Ortoga L, Zhang H, Miao C. Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. Redox Biol 2024; 74: 103194. [PMID: 38852200 DOI: 10.1016/j.redox.2024.103194]

[201] Hahn EL, Halestrap AP, Gamelli RL. Expression of the lactate transporter MCT1 in macrophages. Shock 2000; 13(4): 253-60. [PMID: 10774612 DOI: 10.1097/00024382-200004000-00001]

[202] Brussow J, Feng K, Thiam F, Phogat S, Osei ET. Epithelial-fibroblast interactions in IPF: lessons from in vitro co-culture studies. Differentiation 2023; 134: 11-9. [PMID: 37738701 DOI: 10.1016/j.diff.2023.09.001]

[203] Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016; 533(7603): 420-4. [PMID: 27096365 DOI: 10.1038/nature17946]

[204] Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, et al. Programmable base editing of A•T to G•C in Genomic DNA without DNA cleavage. Nature 2017; 551(7681): 464-71. [PMID: 29160308 DOI: 10.1038/nature24644]

[205] Chen P J, Liu D R. Prime editing for precise and highly versatile genome manipulation. Nat Rev Genet 2023; 24(3): 161-77. [PMID: 36344749 DOI: 10.1038/s41576-022-00541-1]

[206] Sun Y, Chen Y, Peng T. A bioorthogonal chemical reporter for the detection and identification of protein lactylation. Chem Sci 2022; 13(20): 6019-27. [PMID: 35685793 DOI: 10.1039/d2sc00918h]

[207] David R, Richter MP, Beck-Sickinger AG . Expressed protein ligation. Method and applications. Eur J Biochem 2004; 271(4): 663-77. [PMID: 14764082 DOI: 10.1111/j.1432-1033.2004.03978.x]

[208] Currie MF, Singh SK, Ji M, Chatterjee C. The semisynthesis of site-specifically modified histones and histone-based probes of chromatin-modifying enzymes. Methods 2023; 215: 28-37. [PMID: 37244506 DOI: 10.1016/j.ymeth.2023.05.004]

[209] Kim CH, Kang M, Kim HJ, Chatterjee A, Schultz PG. Site-specific incorporation of ε- N-crotonyllysine into histones. Angew Chem Int Ed Engl 2012; 51(29): 7246-9. [PMID: 22689270 DOI: 10.1002/anie.201203349]

[210] Beckert S, Farrahi F, Aslam RS, Scheuenstuhl H, Königsrainer A, et al. Lactate stimulates endothelial cell migration. Wound Repair Regen 2006; 14(3): 321-4. [PMID: 16808811 DOI: 10.1111/j.1743-6109.2006.00127.x]

[211] Schenz J, Heilig L, Lohse T, Tichy L, Bomans K, et al. Extracellular lactate acts as a metabolic checkpoint and shapes monocyte function time dependently. Front Immunol 2021; 12: 729209. [PMID: 34899690 DOI: 10.3389/fimmu.2021.729209]

[212] Halestrap AP, Wilson MC. The monocarboxylate transporter family-role and regulation. IUBMB Life 2012; 64(2): 109-19. [PMID: 22162139 DOI: 10.1002/iub.572]

[213] Balasubramaniam S, Lewis B, Greed L, Meili D, Flier A, et al. Heterozygous monocarboxylate transporter 1 (MCT1, SLC16 A1) deficiency as a cause of recurrent ketoacidosis. In: Morava E, Baumgartner M, Patterson M, Rahman S, Zschocke J, Peters V, editors. JIMD reports. Berlin, Heidelberg: Springer; 2016; 29. pp. 33-8. [PMID: 26608392 DOI: 10.1007/8904_2015_519]

[214] McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, et al. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer 2020; 122(8): 1141-5. [PMID: 32076124 DOI: 10.1038/s41416-020-0727-8]

[215] Katavolos P, Cain G, Farman C, Romero FA, Magnuson S, et al. Preclinical safety assessment of a highly selective and potent dual small-molecule inhibitor of CBP/P300 in rats and dogs. Toxicol Pathol 2020; 48(3): 465-80. [PMID: 32124659 DOI: 10.1177/0192623319898469]

[216] Matsuoka H, Fujimura T, Unami A, Yamada T, Noto T, et al. Novel method for selecting immunosuppressive histone deacetylase (HDAC) inhibitors with minimal thrombocytopenia. Biol Pharm Bull 2008; 31(2): 305-8. [PMID: 18239292 DOI: 10.1248/bpb.31.305]

[217] Duvic M, Vu J. Vorinostat in cutaneous T-cell lymphoma. Drugs Today (Barc) 2007; 43(9): 585-99. [PMID: 17940636 DOI: 10.1358/dot.2007.43.9.1112980]

[218] Osborne B, Bentley NL, Montgomery MK, Turner N. The role of mitochondrial sirtuins in health and disease. Free Radic Biol Med 2016; 100: 164-74. [PMID: 27164052 DOI: 10.1016/j.freeradbiomed.2016.04.197]

[219] Mourits VP, Helder LS, Matzaraki V, Koeken VACM, Groh L, et al. The role of sirtuin 1 on the induction of trained immunity. Cell Immunol 2021; 366: 104393. [PMID: 34147841 DOI: 10.1016/j.cellimm.2021.104393]

[220] King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370(22): 2083-92. [PMID: 24836312 DOI: 10.1056/NEJMoa1402582]

[221] Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med 2019; 381(18): 1718-27. [PMID: 31566307 DOI: 10.1056/NEJMoa1908681]

[222] Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380(26): 2518-28. [PMID: 31112379 DOI: 10.1056/NEJMoa1903076]

[223] Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, et al. Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis. Results of the INJOURNEY trial. Am J Respir Crit Care Med 2018; 197(3): 356-63. [PMID: 28889759 DOI: 10.1164/rccm.201706-1301OC]

[224] Flaherty KR, Fell CD, Huggins JT, Nunes H, Sussman R, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J 2018; 52(2): 1800230. [PMID: 29946005 DOI: 10.1183/13993003.00230-2018]

[225] Thabut G, Crestani B. Treatments for idiopathic pulmonary fibrosis. N Engl J Med 2014; 371(8): 782. [PMID: 25140971 DOI: 10.1056/NEJMc1407776]