Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease

Sheng-Quan Chen; Shu-Jing Zhang; Pei-Jun Liu; Yi Wu; Si-Xuan Li; Jian-Cang Ma; Wu-Jun Li; Shao-Ying Lu; Ji-Chang Wang

doi:10.1016/j.jpha.2025.101457

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Sheng-Quan Chen, Shu-Jing Zhang, Pei-Jun Liu, Yi Wu, Si-Xuan Li, Jian-Cang Ma, Wu-Jun Li, Shao-Ying Lu, Ji-Chang Wang. Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101457

Citation:

Sheng-Quan Chen, Shu-Jing Zhang, Pei-Jun Liu, Yi Wu, Si-Xuan Li, Jian-Cang Ma, Wu-Jun Li, Shao-Ying Lu, Ji-Chang Wang. Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101457

Citation:

Sheng-Quan Chen, Shu-Jing Zhang, Pei-Jun Liu, Yi Wu, Si-Xuan Li, Jian-Cang Ma, Wu-Jun Li, Shao-Ying Lu, Ji-Chang Wang. Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101457

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Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease

doi: 10.1016/j.jpha.2025.101457

a. Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, 710061, China;
b. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, 710061, China;
c. School of Basic Medicine, Xi'an Jiaotong University, Xi’an, 710061, China;
d. Department of Medicine, Xi'an Jiaotong University, Xi’an, 710061, China;
e. Department of Vascular Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi’an, 710001, China;
f. Department of Vascular Surgery, The First Affiliated Hospital of Xi 'an Medical University, Xi’an, 710001, China

Funds:

This work is financially supported by Grants from the National Natural Science Foundation of China (Grant No.: 82473146), the Outstanding Youth Science Fund of Shaanxi Province, China (Grant No.: 2024JC-JCQN-80), the Fundamental Research Funds for the Central Universities, China (Grant No.: xzy012022094), and the Provincial Science and Technology Rising Star, China (Grant No.: 2021KJXX-03).

Received Date: Mar. 24, 2025
Accepted Date: Sep. 25, 2025
Rev Recd Date: Sep. 23, 2025
Available Online: Sep. 28, 2025

Abstract

Abstract

Peripheral artery disease (PAD) is a progressive ischemic condition with limited therapeutic options at advanced stages. Current treatments predominantly target revascularization, often neglecting the metabolic dysregulation underlying this condition. Emerging evidence positions lactate not merely as a glycolytic byproduct but as a critical signaling metabolite that orchestrates neovascularization, vascular remodeling, and immune modulation. Furthermore, lactate-induced histone and nonhistone lactylation dynamically regulate gene expression in ischemic tissues, exerting stage- and cell type-specific effects that may be protective or deleterious. This duality underscores the complexity of lactate signaling and its context-dependent influence on PAD progression. Importantly, lactate and lactylation profoundly affect key vascular cell functions, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages, modulating neovascularization and remodeling. This review summarizes recent advances in the understanding of lactate and lactylation, focusing on their regulatory roles in PAD-associated neovascularization and therapeutic potential for PAD.
- Peripheral artery disease,
- Neovascularization,
- Lactate,
- Lactylation,
- Ischemia

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References(150)

References

[1]	M.D. Gerhard-Herman, H.L. Gornik, C. Barrett, et al., 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, Circulation. 135 (2017) e686-e725.
[2]	C. Adou, J. Magne, N. Gazere, et al., Global epidemiology of lower extremity artery disease in the 21st century (2000-21): a systematic review and meta-analysis, Eur. J. Prev. Cardiol. 31 (2024) 803-811.
[3]	S. Duff, M.S. Mafilios, P. Bhounsule, et al., The burden of critical limb ischemia: a review of recent literature, Vasc. Health Risk Manag. 15 (2019) 187-208.
[4]	M.H. Criqui, V. Aboyans, Epidemiology of peripheral artery disease, Circ. Res. 116 (2015) 1509-1526.
[5]	A. Elbadawi, I.Y. Elgendy, D. Rai, et al., Impact of Hospital Procedural Volume on Outcomes After Endovascular Revascularization for Critical Limb Ischemia, JACC. Cardiovasc. Interv. 14 (2021) 1926-1936.
[6]	T.F. O'Donnell, Jr., J.K. Raines, R.C. Darling, Relationship of muscle surface pH to noninvasive hemodynamic studies in arterial occlusive diseases, Arch. Surg. 114 (1979) 600-604.
[7]	R.B. Khattri, K. Kim, T. Thome, et al., Unique Metabolomic Profile of Skeletal Muscle in Chronic Limb Threatening Ischemia, J. Clin. Med. 2021. https://doi.org/10.3390/jcm10030548.
[8]	L. Li, K. Chen, T. Wang, et al., Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade, Nat. Metab. 2 (2020) 882-892.
[9]	R.A. Irizarry-Caro, M.M. McDaniel, G.R. Overcast, et al., TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation, Proc. Natl. Acad. Sci. U S A. 117 (2020) 30628-30638.
[10]	Z. Yang, C. Yan, J. Ma, et al., Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma, Nat. Metab. 5 (2023) 61-79.
[11]	X. Wang, W. Fan, N. Li, et al., YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2, Genome Biol. 24 (2023), 87.
[12]	M. Certo, A. Llibre, W. Lee, et al., Understanding lactate sensing and signalling, Trends Endocrinol. Metab. 33 (2022) 722-735.
[13]	G.A. Brooks, The Science and Translation of Lactate Shuttle Theory, Cell Metab. 27 (2018) 757-785.
[14]	H.C. Yoo, S.J. Park, M. Nam, et al., A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells, Cell Metab. 31 (2020) 267-283.
[15]	J.D. Rabinowitz, S. Enerback, Lactate: the ugly duckling of energy metabolism, Nat. Metab. 2 (2020) 566-571.
[16]	F. Luo, Z. Zou, X. Liu, et al., Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis, Carcinogenesis. 38 (2017) 615-626.
[17]	K. Ahmed, S. Tunaru, C. Tang, et al., An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81, Cell Metab. 11 (2010) 311-319.
[18]	T.P. Brown, V. Ganapathy, Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon, Pharmacol Ther. 206 (2020), 107451.
[19]	M. Harun-Or-Rashid, D.M. Inman, Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma, J. Neuroinflammation. 15 (2018), 313.
[20]	B. Bartoloni, M. Mannelli, T. Gamberi, et al., The Multiple Roles of Lactate in the Skeletal Muscle, Cells. 13 (2024), 1177.
[21]	D. Zhang, Z. Tang, H. Huang, et al., Metabolic regulation of gene expression by histone lactylation, Nature. 574 (2019) 575-580.
[22]	D.O. Gaffney, E.Q. Jennings, C.C. Anderson, et al., Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes, Cell Chem. Biol. 27 (2020) 206-213.
[23]	N. Rabbani, M. Xue, P.J. Thornalley, Activity, regulation, copy number and function in the glyoxalase system, Biochem. Soc. Trans. 42 (2014) 419-424.
[24]	J. Chen, D. Zhao, Y. Wang, et al., Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis, Adv. Sci. (Weinh). 2024. https://doi.org/10.1002/advs.202406333.
[25]	Y. Hu, Z. He, Z. Li, et al., Lactylation: the novel histone modification influence on gene expression, protein function, and disease, Clin. Epigenetics. 16 (2024), 72.
[26]	S. Manickavinayaham, R. Velez-Cruz, A.K. Biswas, et al., E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair, Nat. Commun. 10 (2019), 4951.
[27]	Z. Li, T. Gong, Q. Wu, et al., Lysine lactylation regulates metabolic pathways and biofilm formation in Streptococcus mutans, Sci Signal. 16 (2023), eadg1849.
[28]	Z. Niu, C. Chen, S. Wang, et al., HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription, Nat. Commun. 15 (2024), 3561.
[29]	B. Xie, M. Zhang, J. Li, et al., KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis, Proc. Natl. Acad. Sci. U S A. 121 (2024), e2314128121.
[30]	Y. Mao, J. Zhang, Q. Zhou, et al., Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation, Cell Res. 34 (2024) 13-30.
[31]	Z. Fan, Z. Liu, N. Zhang, et al., Identification of SIRT3 as an eraser of H4K16la, iScience. 26 (2023), 107757.
[32]	X. Hu, X. Huang, Y. Yang, et al., Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader, Nucleic Acids Res. 52 (2024) 5529-5548.
[33]	N. Narula, A.J. Dannenberg, J.W. Olin, et al., Pathology of Peripheral Artery Disease in Patients With Critical Limb Ischemia, J. Am. Coll. Cardiol. 72 (2018) 2152-2163.
[34]	M.M. McDermott, L. Ferrucci, M. Gonzalez-Freire, et al., Skeletal Muscle Pathology in Peripheral Artery Disease: A Brief Review, Arterioscler. Thromb. Vasc. Biol. 40 (2020) 2577-2585.
[35]	Y. Matsubara, T. Matsumoto, Y. Aoyagi, et al., Sarcopenia is a prognostic factor for overall survival in patients with critical limb ischemia, J. Vasc. Surg. 61 (2015) 945-950.
[36]	G. Lundberg, E. Wahlberg, J. Swedenborg, et al., Continuous assessment of local metabolism by microdialysis in critical limb ischaemia, Eur. J. Vasc. Endovasc. Surg. 19 (2000) 605-613.
[37]	C. Ruangsetakit, K. Chinsakchai, P. Mahawongkajit, et al., Transcutaneous oxygen tension: a useful predictor of ulcer healing in critical limb ischaemia, J. Wound Care. 19 (2010) 202-206.
[38]	H. Hagberg, Intracellular pH during ischemia in skeletal muscle: relationship to membrane potential, extracellular pH, tissue lactic acid and ATP, Pflugers Arch. 404 (1985) 342-347.
[39]	M. Tozzi, E. Muscianisi, G. Piffaretti, et al., Microdialysis assessment of peripheral metabolism in critical limb ischemia after endovascular revascularization, Ann. Surg. Innov. Res. 2009. https://doi.org/10.1186/1750-1164-3-17.
[40]	L. Liasis, G. Malietzis, G. Galyfos, et al., The emerging role of microdialysis in diabetic patients undergoing amputation for limb ischemia, Wound Repair Regen. 24 (2016) 1073-1080.
[41]	M. Heil, W. Schaper, Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis), Circ. Res. 95 (2004) 449-458.
[42]	C. Urbich, S. Dimmeler, Endothelial progenitor cells: characterization and role in vascular biology, Circ. Res. 95 (2004) 343-353.
[43]	W. Chen, P. Xia, H. Wang, et al., The endothelial tip-stalk cell selection and shuffling during angiogenesis, J. Cell Commun. Signal. 13 (2019) 291-301.
[44]	P. Carmeliet, R.K. Jain, Molecular mechanisms and clinical applications of angiogenesis, Nature. 473 (2011) 298-307.
[45]	J.P. Cooke, S. Meng, Vascular Regeneration in Peripheral Artery Disease, Arterioscler. Thromb. Vasc. Biol. 40 (2020) 1627-1634.
[46]	A. Helisch, W. Schaper, Arteriogenesis: the development and growth of collateral arteries, Microcirculation. 10 (2003) 83-97.
[47]	M.A. Ziegler, M.R. Distasi, R.G. Bills, et al., Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion, Microcirculation. 17 (2010) 3-20.
[48]	N. Resnick, S. Einav, L. Chen-Konak, et al., Hemodynamic forces as a stimulus for arteriogenesis, Endothelium. 10 (2003) 197-206.
[49]	B. Park, A. Hoffman, Y. Yang, et al., Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice, J. Vasc. Surg. 51 (2010) 165-173.
[50]	E. Vagesjo, K. Parv, D. Ahl, et al., Perivascular Macrophages Regulate Blood Flow Following Tissue Damage, Circ. Res. 128 (2021) 1694-1707.
[51]	N. van Royen, I. Hoefer, I. Buschmann, et al., Exogenous application of transforming growth factor beta 1 stimulates arteriogenesis in the peripheral circulation, FASEB J. 16 (2002) 432-434.
[52]	S. Belmadani, K. Matrougui, C. Kolz, et al., Amplification of coronary arteriogenic capacity of multipotent stromal cells by epidermal growth factor, Arterioscler. Thromb. Vasc. Biol, 29 (2009) 802-808.
[53]	E. Deindl, I.E. Hoefer, B. Fernandez, et al., Involvement of the fibroblast growth factor system in adaptive and chemokine-induced arteriogenesis, Circ. Res. 92 (2003) 561-568.
[54]	I.E. Hoefer, N. van Royen, J.E. Rectenwald, et al., Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis, Circulation, 105 (2002) 1639-1641.
[55]	D. Scholz, W. Ito, I. Fleming, et al., Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis), Virchows Arch. 436 (2000) 257-270.
[56]	J.L. Ungerleider, T.D. Johnson, M.J. Hernandez, et al., Extracellular Matrix Hydrogel Promotes Tissue Remodeling, Arteriogenesis, and Perfusion in a Rat Hindlimb Ischemia Model, JACC Basic Transl. Sci. 1 (2016) 32-44.
[57]	T. Asahara, T. Takahashi, H. Masuda, et al., VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells, EMBO J. 18 (1999) 3964-3972.
[58]	D.J. Ceradini, A.R. Kulkarni, M.J. Callaghan, et al., Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1, Nat. Med. 10 (2004) 858-864.
[59]	J.C. Kovacic, D.W. Muller, R.M. Graham, Actions and therapeutic potential of G-CSF and GM-CSF in cardiovascular disease, J. Mol. Cell Cardiol. 42 (2007) 19-33.
[60]	T. Takahashi, C. Kalka, H. Masuda, et al., Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization, Nat. Med. 5 (1999) 434-438.
[61]	D. Ribatti, A. Vacca, B. Nico, et al., Postnatal vasculogenesis, Mech. Dev. 100 (2001) 157-163.
[62]	L. Hu, S.C. Dai, X. Luan, et al., Dysfunction and Therapeutic Potential of Endothelial Progenitor Cells in Diabetes Mellitus, J. Clin. Med. Res. 10 (2018) 752-757.
[63]	C. Jung, A. Rafnsson, A. Shemyakin, et al., Different subpopulations of endothelial progenitor cells and circulating apoptotic progenitor cells in patients with vascular disease and diabetes, Int. J. Cardiol. 143 (2010) 368-372.
[64]	K. Lin, P.P. Hsu, B.P. Chen, et al., Molecular mechanism of endothelial growth arrest by laminar shear stress, Proc. Natl. Acad. Sci. U S A. 97 (2000) 9385-9389.
[65]	J. Kim, Y.H. Kim, J. Kim, et al., YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation, J. Clin. Invest. 127 (2017) 3441-3461.
[66]	M.J. Goumans, P. Ten Dijke, TGF-β Signaling in Control of Cardiovascular Function, Cold Spring Harb. Perspect. Biol. 2018. https://doi.org/10.1101/cshperspect.a022210.
[67]	J.J. Olsen, S. Pohl, A. Deshmukh, et al., The Role of Wnt Signalling in Angiogenesis, Clin. Biochem. Rev. 38 (2017) 131-142.
[68]	M.E. Pitulescu, I. Schmidt, B.D. Giaimo, et al., Dll4 and Notch signalling couples sprouting angiogenesis and artery formation, Nat. Cell Biol. 19 (2017) 915-927.
[69]	K. De Bock, M. Georgiadou, S. Schoors, et al., Role of PFKFB3-driven glycolysis in vessel sprouting, Cell, 154 (2013) 651-663.
[70]	O.A. Stone, M. El-Brolosy, K. Wilhelm, et al., Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells, Nat. Commun. 9 (2018), 4077.
[71]	X. Li, A. Kumar, P. Carmeliet, Metabolic Pathways Fueling the Endothelial Cell Drive, Annu. Rev. Physiol. 81 (2019) 483-503.
[72]	M. Jabs, A.J. Rose, L.H. Lehmann, et al., Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart, Circulation. 137 (2018) 2592-2608.
[73]	Z. Cai, G. Satyanarayana, P. Song, et al., Regulation of Ptbp1-controlled alternative splicing of pyruvate kinase muscle by Liver kinase b1 governs vascular smooth muscle cell plasticity in vivo, Cardiovasc. Res. 2024. https://doi.org/10.1093/cvr/cvae187.
[74]	J.V. Ashraf, A. Al Haj Zen, Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis, Int. J. Mol. Sci. 22 (2021), 10585.
[75]	M.R. Bennett, S. Sinha, G.K. Owens, Vascular Smooth Muscle Cells in Atherosclerosis, Circ. Res. 118 (2016) 692-702.
[76]	M. Liu, D. Gomez, Smooth Muscle Cell Phenotypic Diversity, Arterioscler. Thromb. Vasc. Biol. 39 (2019) 1715-1723.
[77]	M. Garcia-Miguel, J.A. Riquelme, I. Norambuena-Soto, et al., Autophagy mediates tumor necrosis factor-α-induced phenotype switching in vascular smooth muscle A7r5 cell line, PLoS One, 13 (2018), e0197210.
[78]	B. Yu, M.M. Wong, C.M. Potter, et al., Vascular Stem/Progenitor Cell Migration Induced by Smooth Muscle Cell-Derived Chemokine (C-C Motif) Ligand 2 and Chemokine (C-X-C motif) Ligand 1 Contributes to Neointima Formation, Stem Cells, 34 (2016) 2368-2380.
[79]	Y. Okada, S. Katsuda, Y. Matsui, et al., Collagen synthesis by cultured arterial smooth muscle cells during spontaneous phenotypic modulation, Acta. Pathol. Jpn. 40 (1990) 157-164.
[80]	R.N. Weinreb, K. Kashiwagi, F. Kashiwagi, et al., Prostaglandins increase matrix metalloproteinase release from human ciliary smooth muscle cells, Invest. Ophthalmol. Vis. Sci. 38 (1997) 2772-2780.
[81]	H.J. Sun, X.S. Ren, X.Q. Xiong, et al., NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension, Cell Death Dis. 8 (2017), e3074.
[82]	C.P. Mack, J.S. Hinson, Regulation of smooth muscle differentiation by the myocardin family of serum response factor co-factors, J. Thromb. Haemost. 3 (2005) 1976-1984.
[83]	J.C. Wang, G.Y. Li, B. Wang, et al., Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation, J. Exp. Clin. Cancer Res. 38 (2019), 235.
[84]	F. Dandre, G.K. Owens, Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes, Am. J. Physiol. Heart Circ. Physiol. 286 (2004) H2042-2051.
[85]	C. Kupatt, R. Hinkel, A. Pfosser, et al., Cotransfection of vascular endothelial growth factor-A and platelet-derived growth factor-B via recombinant adeno-associated virus resolves chronic ischemic malperfusion role of vessel maturation, J. Am. Coll. Cardiol. 56 (2010) 414-422.
[86]	R. Cao, E. Brakenhielm, R. Pawliuk, et al., Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2, Nat. Med. 9 (2003) 604-613.
[87]	X. Dai, J.E. Faber, Endothelial nitric oxide synthase deficiency causes collateral vessel rarefaction and impairs activation of a cell cycle gene network during arteriogenesis, Circ. Res. 106 (2010) 1870-1881.
[88]	Y. Ma, L. Jia, Y. Wang, et al., Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3, Arterioscler. Thromb. Vasc. Biol. 41 (2021) 1710-1723.
[89]	A.C. Bruce, M.R. Kelly-Goss, J.L. Heuslein, et al., Monocytes are recruited from venules during arteriogenesis in the murine spinotrapezius ligation model, Arterioscler. Thromb. Vasc. Biol. 34 (2014) 2012-2022.
[90]	A. la Sala, L. Pontecorvo, A. Agresta, et al., Regulation of collateral blood vessel development by the innate and adaptive immune system, Trends Mol. Med. 18 (2012) 494-501.
[91]	A. Hamm, L. Veschini, Y. Takeda, et al., PHD2 regulates arteriogenic macrophages through TIE2 signalling, EMBO Mol. Med. 5 (2013) 843-857.
[92]	K.L. Spiller, R.R. Anfang, K.J. Spiller, et al., The role of macrophage phenotype in vascularization of tissue engineering scaffolds, Biomaterials. 35 (2014) 4477-4488.
[93]	F.O. Martinez, S. Gordon, The M1 and M2 paradigm of macrophage activation: time for reassessment, F1000Prime Rep. 6 (2014), 13.
[94]	A. Ntokou, J.M. Dave, A.C. Kauffman, et al., Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension, JCI. Insight. 6 (2021), e139067.
[95]	Y. Ji, E.M. Lisabeth, R.R. Neubig, Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling, Mol. Pharmacol. 100 (2021) 53-60.
[96]	C.B. Anders, T.M.W. Lawton, H.L. Smith, et al., Use of integrated metabolomics, transcriptomics, and signal protein profile to characterize the effector function and associated metabotype of polarized macrophage phenotypes, J Leukoc Biol. 111 (2022) 667-693.
[97]	R.C. Sainson, D.A. Johnston, H.C. Chu, et al., TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype, Blood. 111 (2008) 4997-5007.
[98]	O.H. Lee, S.K. Bae, M.H. Bae, et al., Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models, Br. J. Cancer. 82 (2000) 385-391.
[99]	V.B. Mehta, G.E. Besner, HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways, Growth Factors. 25 (2007) 253-263.
[100]	Y. Carmi, E. Voronov, S. Dotan, et al., The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis, J Immunol. 183 (2009) 4705-4714.
[101]	N. Jetten, S. Verbruggen, M.J. Gijbels, et al., Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo, Angiogenesis. 17 (2014) 109-118.
[102]	Y. Wang, Y. Fan, H. Liu, Macrophage Polarization in Response to Biomaterials for Vascularization, Ann. Biomed. Eng. 49 (2021) 1992-2005.
[103]	Q. Wang, H. Ni, L. Lan, et al., Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages, Cell Res. 20 (2010) 701-712.
[104]	S. Beckert, F. Farrahi, R.S. Aslam, et al., Lactate stimulates endothelial cell migration, Wound Repair Regen. 14 (2006) 321-324.
[105]	V.B. Kumar, R.I. Viji, M.S. Kiran, et al., Endothelial cell response to lactate: implication of PAR modification of VEGF, J. Cell Physiol. 211 (2007) 477-485.
[106]	C.J. De Saedeleer, T. Copetti, P.E. Porporato, et al., Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells, PLoS One, 7 (2012), e46571.
[107]	D.C. Lee, H.A. Sohn, Z.Y. Park, et al., A lactate-induced response to hypoxia, Cell, 161 (2015) 595-609.
[108]	F. Vegran, R. Boidot, C. Michiels, et al., Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis, Cancer Res. 71 (2011) 2550-2560.
[109]	G.X. Ruan, A. Kazlauskas, Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis, J. Biol. Chem. 288 (2013) 21161-21172.
[110]	M. Fan, K. Yang, X. Wang, et al., LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS, Shock. 58 (2022) 304-312.
[111]	M. Fan, K. Yang, X. Wang, et al., Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction, Sci. Adv. 9 (2023), eadc9465.
[112]	Y. Wang, L. Chen, M. Zhang, et al., Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway, Atherosclerosis, 375 (2023) 45-58.
[113]	M. Dong, Y. Zhang, M. Chen, et al., ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT, Acta. Pharm. Sin. B. 14 (2024) 3027-3048.
[114]	T.M. Butler, M.J. Siegman, High-energy phosphate metabolism in vascular smooth muscle, Annu. Rev. Physiol. 47 (1985) 629-643.
[115]	J. Shi, Y. Yang, A. Cheng, et al., Metabolism of vascular smooth muscle cells in vascular diseases, Am. J. Physiol. Heart Circ. Physiol. 319 (2020) H613-H631.
[116]	J.H. Kim, K.H. Bae, J.K. Byun, et al., Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration, Biochem. Biophys. Res. Commun. 492 (2017) 41-47.
[117]	J. Niu, C. Wu, M. Zhang, et al., κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling, Aging (Albany NY). 13 (2021) 14355-14371.
[118]	X. Zhao, F. Tan, X. Cao, et al., PKM2-dependent glycolysis promotes the proliferation and migration of vascular smooth muscle cells during atherosclerosis, Acta. Biochim. Biophys. Sin. (Shanghai), 52 (2020) 9-17.
[119]	L. Yang, L. Gao, T. Nickel, et al., Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells, Circ. Res. 121 (2017) 1251-1262.
[120]	J. Yang, G.R. Gourley, A. Gilbertsen, et al., High Glucose Levels Promote Switch to Synthetic Vascular Smooth Muscle Cells via Lactate/GPR81, Cells. 13 (2024), 236.
[121]	Y. Hu, C. Zhang, Y. Fan, et al., Lactate promotes vascular smooth muscle cell switch to a synthetic phenotype by inhibiting miR-23b expression, Korean J. Physiol. Pharmacol. 26 (2022) 519-530.
[122]	X. Li, M. Chen, X. Chen, et al., TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation, Eur. Heart J. 45 (2024) 4219-4235.
[123]	X. Xu, D.D. Zhang, P. Kong, et al., Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia, Cell Rep. 42 (2023), 112869.
[124]	W. Ma, K. Jia, H. Cheng, et al., Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation, Circ Res. 134 (2024) 1427-1447.
[125]	O.R. Colegio, N.Q. Chu, A.L. Szabo, et al., Functional polarization of tumour-associated macrophages by tumour-derived lactic acid, Nature. 513 (2014) 559-563.
[126]	K. Yang, J. Xu, M. Fan, et al., Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling, Front. Immunol. 11 (2020), 587913.
[127]	N. Liu, J. Luo, D. Kuang, et al., Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression, J. Clin. Invest. 129 (2019) 631-646.
[128]	J. Zhang, J. Muri, G. Fitzgerald, et al., Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization, Cell Metab. 31 (2020) 1136-1153.
[129]	X. Chu, C. Di, P. Chang, et al., Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock, Front. Immunol. 12 (2021), 786666.
[130]	R.Y. Pan, L. He, J. Zhang, et al., Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease, Cell Metab. 34 (2022) 634-648.
[131]	T. Desgeorges, E. Galle, J. Zhang, et al., Histone lactylation in macrophages is predictive for gene expression changes during ischemia induced-muscle regeneration, Mol. Metab. 83 (2024), 101923.
[132]	L. Chen, M. Zhang, X. Yang, et al., Methyl-CpG-binding 2 K271 lactylation-mediated M2 macrophage polarization inhibits atherosclerosis, Theranostics, 14 (2024) 4256-4277.
[133]	B. Cui, Y. Luo, P. Tian, et al., Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells, J Clin Invest. 129 (2019) 1030-1046.
[134]	H. Chen, Y. Li, H. Li, et al., NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance, Nature. 631 (2024) 663-669.
[135]	J. Wei, X.Y. Chen, Z.J. Wang, et al., Galloflavin mitigates acute kidney injury by suppressing LDHA-dependent macrophage glycolysis, Int. Immunopharmacol. 150 (2025), 114265.
[136]	B. Alobaidi, S.M. Hashimi, A.I. Alqosaibi, et al., Targeting the monocarboxylate transporter MCT2 and lactate dehydrogenase A LDHA in cancer cells with FX-11 and AR-C155858 inhibitors, Eur. Rev. Med. Pharmacol. Sci. 27 (2023) 6605-6617.
[137]	B. Pajak, E. Siwiak, M. Soltyka, et al., 2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents, Int. J. Mol. Sci. 21 (2019), 234.
[138]	T. Tataranni, C. Piccoli, Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications, Oxid. Med. Cell. Longev. 2019. https://doi.org/10.1155/2019/8201079.
[139]	A. Silva, B. Antunes, A. Batista, et al., In Vivo Anticancer Activity of AZD3965: A Systematic Review, Molecules. 2021. https://doi.org/10.3390/molecules27010181.
[140]	F. Zhang, T. Gu, J. Li, et al., Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression, Hum. Cell. 38 (2024), 11.
[141]	M.C. Choi, S.K. Kim, Y.J. Choi, et al., Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells, Arch. Pharm. Res. 46 (2023) 907-923.
[142]	N. Zhang, Y. Zhang, J. Xu, et al., α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure, Cell Res. 33 (2023) 679-698.
[143]	D. Benjamin, D. Robay, S.K. Hindupur, et al., Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells, Cell Rep. 25 (2018) 3047-3058.
[144]	B. Nancolas, L. Guo, R. Zhou, et al., The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters, Biochem J. 473 (2016) 929-936.
[145]	Z. Shen, L. Jiang, Y. Yuan, et al., Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury, CNS Neurosci Ther. 21 (2015) 271-279.
[146]	J. Yuan, M. Yang, Z. Wu, et al., The Lactate-Primed KAT8-PCK2 Axis Exacerbates Hepatic Ferroptosis During Ischemia/Reperfusion Injury by Reprogramming OXSM-Dependent Mitochondrial Fatty Acid Synthesis, Adv. Sci. (Weinh). 12 (2025), e2414141.
[147]	M. Sun, Y. Zhang, R. Mao, et al., MeCP2 Lactylation Protects against Ischemic Brain Injury by Transcriptionally Regulating Neuronal Apoptosis, Adv. Sci. (Weinh). 12(2025), e2415309.
[148]	L. Wang, D. Li, F. Yao, et al., Serpina3k lactylation protects from cardiac ischemia reperfusion injury, Nat. Commun. 16 (2025), 1012.
[149]	H. She, Y. Hu, G. Zhao, et al., Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming, Adv. Sci. (Weinh). 11 (2024), e2409499.
[150]	I. Elia, M. Rossi, S. Stegen, et al., Breast cancer cells rely on environmental pyruvate to shape the metastatic niche, Nature. 568 (2019) 117-121.