
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12327-4
10.1016/j.heliyon.2024.e36296
e36296
Review Article
The role of nonhistone lactylation in disease
Yu Hao a1
Zhu Tingting ab1
Ma Dongwen ab
Cheng Xiaohan ac
Wang Shengjia ab
Yao Yongzhong yyz1006@hotmail.com
abc⁎
a Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
b Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, School of Medicine, Southeast University, China
c Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, China
⁎ Corresponding author. Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, 210008, Nanjing, Jiangsu, China. yyz1006@hotmail.com
1 These authors contributed equally to this work and share first authorship.

18 8 2024
30 9 2024
18 8 2024
10 18 e3629618 5 2024
12 8 2024
13 8 2024
© 2024 Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
In 2019, a novel post-translational modification termed lactylation was identified, which established a connection among lactate, transcriptional regulation and epigenetics. Lactate, which is traditionally viewed as a metabolic byproduct, is now recognized for its significant functional role, including modulating the tumor microenvironment, engaging in signaling and interfering in immune regulation. While research on lactylation (KLA) is advancing, the focus has primarily been on histone lactylation. This paper aims to explore the less-studied area of nonhistone lactylation, highlighting its involvement in certain diseases and physiological processes. Additionally, the clinical relevance and potential implications of nonhistone lactylation will be discussed.

Keywords

Lactate
Lactylation
Nonhistone
Cancer
Inflammation
==== Body
pmc1 Introduction

Since its discovery in 1780, lactic acid has been considered a byproduct of metabolism, a metabolic waste product produced by strenuous exercise or hypoxic conditions [1]. However, with decades of research, there has been a fundamental change in the way we think about lactate. The lactate shuttle hypothesis suggests that lactate acts as a bridge molecule that coordinates signaling between different cells, tissues, and organs [2]. Lactate can act as a metabolic substance that is autonomously taken up by tumors, thereby altering the tumor microenvironment [3,4]. Lactic acid can act as a signaling molecule and participate in signaling pathways to regulate gene expression and functional changes in immune cells, macrophages, cancer cells, fibroblasts, etc., which play indispensable roles in tumors, inflammation and metabolism [[5], [6], [7], [8]].

A new protein post-translational modification (PTM), lysine lactylation (Kla), discovered by Zhang et al., in 2019, has provided new research ideas on the physiopathological functions of lactate [9]. Many studies on histone lactylation have been carried out. Stimulation of histone lactylation can promote macrophage polarization, which is involved in tumor development [10]. It also directly drives the expression of downstream genes, such as Arg1 and YTHDF2, to regulate the glycolytic pathway,Jak-STAT pathway and PI3K-Akt-GSK pathway [9,11,12].In 2020, researchers used high-throughput sequencing to sequence the lactating sites of botrytis cinerea and found that there were a large number of lacylation sites [13]. In a further investigation of the human proteome, the researchers determined that lacylation exists not only in histones, but also widely in non-histones [14,15]. The discovery of nonhistone lactylation has expanded the understanding of lactylation, allowing us to move away from viewing it solely as a modification of chromatin. Like histone lactylation, nonhistone lactonization exhibits spatiotemporal dynamics [16]. We hope that the lactylation of nonhistone proteins can be a target for disease treatment and provide therapeutic assistance.

2 Lactic acid and nonhistone modifications

Warburg noted that even in the presence of an adequate supply of oxygen, tumor cells still prefer glycolysis for energy over oxidative phosphorylation (OXPHOS), which provides a more efficient energy supply. This phenomenon is known as the Warburg effect [17]. The Warburg effect, in addition to providing tumor cells with large amounts of adenine nucleoside triphosphate needed for growth and proliferation, also provides large amounts of lactate. Lactate, an inevitable product of the glycolytic pathway, is a regulatory molecule for metabolism, the immune response and intercellular communication [18].Lactate metabolism in glycolytic and oxidizing tumor cells is shown in Fig. 1.Fig. 1 Lactate metabolism in glycolytic tumor cells and oxidative tumor cells.

Under hypoxia, NADH and pyruvate are reduced to lactate, and ultimately, one molecule of glucose will produce two ATP molecules and two lactate molecules. Glycolytic tumor cells transport lactate into EMT via mct4, whereas oxidative tumor cells take up lactate via mct1 and generate energy via OXPHOS.

Fig. 1

Fig. 2 Production of non-histone lactylations.

Lactate enters cells via MCT1 and later becomes Kla via GLO2. Glucose enters the cell via GLUT1 and later becomes pyruvate via the EMP pathway, eventually pyruvate becomes lactate through LDH.P300/CBP lactylates nonhistone proteins and SIRT can de-lactylated it.

Fig. 2

Lactic acid is partially transferred from lactoyl glutathione (LGSH) to protein lysine residues to form lactylation modifications.The production process of nonhistone lactylation is shown in Table 2.Although not at the same levels, sequencing of lactylation in the plants Funga pathogen Botrytis cinerea, rice, Trypanosoma brucei and humans demonstrated the evolutionary conservation and biological consistency of lactylation (see Fig. 2). In humans, researchers have characterized the lactylproteome of the human body through the cyclic imposition of lactyllysine via tandem mass spectrometry, revealing that outside of histones, lactylation occurs widely in the human proteome and is enriched in the glycolytic pathway [14]. In the genomic lactate group analysis for hepatitis-associated hepatocellular carcinoma (HCC), a total of 9275 Kla sites were identified, of which 9256 were located in nonhistone proteins. Researchers further clarified that PKM2 lactylation can regulate hepatocellular carcinoma cell proliferation and metastasis and determined that nonhistone protein lactylation can promote the proliferation and migration of tumors [15]. In acute ischemic stroke (AIS), researchers identified a total of 1003 Kla sites on 469 proteins in the cerebral cortex of a mouse model of cerebral ischemia/reperfusion injury (CIRI), and these sites were associated with the mitochondrial apoptotic pathway and mediated neuronal death [21].Lactylation content determined by genome sequencing ispresented in Table 1.The study of the lactylation of nonhistone proteins extends the mechanistic study of lactic acid in human diseases, as lactic acid functions not only as a metabolite or signaling molecule but also as a modifying molecule that plays different roles in proteins.Table 1 Lactylation content determined by genome sequencing.

Table 1Source	Number	Sites	Enrich	
HCC [15]	9140	9275	Metabolic pathways	
FHC/SW480 [22]	444	637	glycolysis pathway	
Cerebral Endothelium of CIRI Rats [21]	469	1003	Mitochondrial apoptosis pathway	
Botrytis cinerea [13]	166	273	Protein synthesis	
Rice [20]	342	638	Central carbon metabolism and protein biosynthesis	
Protozoan Parasite Trypanosoma brucei [19]	257	387	Glucose metabolism	
mouse prefrontal cortex [23]	63	N/A	Nucleosome-and histone-related biological processes	
human lungs [24]	451	724	RNA splicing, actin filament organization, and neutrophil degranulation	
N/A:Not Available.

Table 2 The regulation of nonhistone lactylation in cell lines and diseases.

Table 2Gene	Cell lines	Lactylation protein(s)/site(s)	Function and mechanism	Writer/Eraser	Disease	
METTL16 [61]	HGC-27	K229	Cuproptosis	SIRT2	Gastric cancer	
YY1 [39]	HMC3	K183	Neovascularizationupregulate FGF2	P300	Retinopathy of premary	
PKM2 [46]	293T	K62	Inflammation
Wound healing	N/A	Inflammatory	
Snail1 [71]	HUVEC	N/A	EndoMT upregulate Cdh5,Kdr
downregulate Acta2,Fn1,S100a4	MCT1	Myocardial infarction	
FASN [73]	AML-12	K673	hepatocyte lipid accumulation	MPC1	NAFLD	
Vps34 [74]	HEK293T; H1299	K356
K781	Autophagic flux endolysosomal trafficking
skeletal muscle homeostasis	KAT5/TIP60	lung cancer gastric cancer	
α-MHC [70]	H9c2	K1897	Reduces α-MHC-Titin interaction	p300; SIRT1; LDHA	Heart failur	
METTL3 [55]	293T	K281
K345	m6A modification
immunosuppression	N/A	Colon cancer	
HMGB1 [48,49]	RAW 264.7	N/A	Downregulate VE-cadherin,Claudin 5 upregulate ICAM1	P300/CBP
HSPA12A	Sepsis
LI/R	
MOESIN [50]	Treg	K72	Regulates Treg cells enhances TGF-β signaling
anti-PD-1 treatment	N/A	Liver cancer	
Fis1 [58]	N/A	K20	Mitochondrial apoptosis	PDHA1	SAKI	
Mecp2 [69]	MAECs	k271	Downregulate Ereg inflammation repair	N/A	ASCVD	
HIF-1α [40,75]	N/A	N/A	downregulate sema3A upregulate VEGFA
VE-cadherin	MCT1; MCT4	Prostate cancer	
PFKP [22]	SW480	K688	The glycolysis pathway	N/A	Colorectal cancer	
CCNE2 [38]	Huh7	K348	Tumor cell proliferation migration invasion	SIRT3	HCC	
PDHA1 [30]	N/A	K336	Inhibiting OXPHOS	AARS2; SIRT3	endurance
exercise	
CPT2 [30]	N/A	K457/8	Inhibiting OXPHOS	AARS2; SIRT3	endurance exercise	
MRE11 [60]	N/A	K673	Homologous recombination chemoresistance	CBP/LDH	N/A	
IDH3G [62]	H1975	N/A	Glycolytic pathway	BZW2	Lung Adenocarcinoma	
LCP1 [67]	PC12	N/A	Cell viability	N/A	Cerebral infarction	
DCBLD1 [65]	SiHa	K172	active pentose phosphate pathway
autophagic degradation	N/A	Cervical cancer	
METTL3 [55]	293T	N/A	enhance the capture of m6A-modified RNA	N/A	colon tumor	
N/A:Not Available.

3 Functions of nonhistone lactylation

3.1 Nonhistone lactylation and metabolic regulation

Lactate is not only a metabolite but also an energy substrate [25]. Under aerobic conditions, pyruvate produced by glycolysis generates carbon dioxide and oxygen through OXPHOS. However, under hypoxia, nicotinamide adenine dinucleotide (NADH) and pyruvate are reduced to lactate, and ultimately, one molecule of glucose will produce two adenosine triphosphates (ATP) and two lactate molecules [26,27]. However, in the determination of circulating metabolites in mice, it was determined that lactate can also be a major source of carbon for the TCA cycle and thus becomes a major source of energy [28]. The role of lactate in metabolic regulation deserves to be explored in depth, and lactylation provides a new direction for research. In 2020, James et al. identified 350 Kla proteins, which were mainly enriched in the glycolytic pathway, after analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases in a nonenzymatic lactylation study [29]. Researchers further determined from glycolytic enzymes that lactate is partially transferred from LGSH to protein lysine residues to undergo lactylation, a process regulated by glyoxalase 2 (GLO2). This suggests that lactylation is enriched in glycolytic enzymes and can lead to reduced glycolytic output. In contrast, another study showed that hypoxia promotes the expression of mitochondrial alanyl-tRNA synthetase (AARS2), which lactylates PDHA1 K336 and carnitine palmitoyltransferase 2 (CPT2) K457/8 in the pyruvate dehydrogenase complex, leading to their inactivation and inhibition of OXPHOS by restricting the influx of acetyl-CoA for the oxidation of pyruvate and fatty acids. Moreover, SIRT3, which is an essential part of the pyruvate dehydrogenase complex, is a key component of OXPHOS. SIRT3, in turn, reverses PDHA1 and CPT2 lactylation, thereby activating OXPHOS [30]. This suggests that intracellular nonhistone lactonation plays a key regulatory role between aerobic and anaerobic metabolism and plays a critical role in the adaptation of cells to different energy demands and environmental conditions, providing a flexible and fine-grained means of regulating metabolic homeostasis in the cell.

3.2 Nonhistone lactylation and cell signaling

Lactate can function as a signaling molecule in the regulation of cancer and cardiovascular disease-related diseases [31,32]. Lactate causes a decrease in cAMP levels by activating G protein-coupled receptor 81 (GPR81) [33]. This pathway includes autocrine and paracrine pathways that can ultimately promote angiogenesis, immune evasion, the inflammatory response, and neurodevelopment [[34], [35], [36], [37]].

JIN et al. studied the role of SIRT3 in lactylation in HCC and reported that SIRT3 regulates lactylation and that the main lactylation proteins regulated are related to the cell cycle. For example, the cell cycle protein E2 (CCNE2) and lactylation of this protein are clearly associated with apoptosis in HCC [38].

The significant overlap of nonhistone lactylation sites with key nodes of several signaling pathways, including TGF-β and autophagy, suggests an important regulatory role for this form of modification in signaling [7,39,40]. Among them, PIK3C3/VPS34 lactylation can promote autophagy through the degradation of epidermal growth factor receptor (EGFR) and decreased hydrolytic maturation of cathepsin D (CTSD) [7]. Future studies need to further elucidate the regulatory mechanisms involved in nonhistone lactylation and signaling pathways, as well as their roles in disease development, which will help reveal potential therapeutic targets and biological mechanisms involved.

3.3 Nonhistone lactylation and immunomodulation

The expression of key proteins in immune cells, such as T cells, B cells and macrophages, is affected by lactate, which has been determined to be closely linked to immune cell function [25,27,41,42]. By regulating the level of lactylation of these proteins, nonhistone lactylation can be involved in key processes such as activation, proliferation and differentiation of immune cells [23,43].

In the immune system, macrophages, as important immune cells, are involved in the clearance of pathogens and immunoregulation. Macrophages require large amounts of energy to maintain their active state during infection and inflammatory states, and nonhistone lactylation has been associated with the regulation of macrophage energy metabolism. PKM2 is a key enzyme in glycolysis and plays a critical role in the regulation of the Warburg effect. PKM2 can promote macrophage differentiation through the exosomal pathway or regulate inflammatory vesicle activation in macrophages by mediating glycolysis [44,45]. Wang et al. identified PKM2 lactylation by mass spectrometry, and lactate revealed the role of PKM2 lactylation in the adaptation to inflammatory metabolism in proinflammatory macrophages by increasing PKM2 lactylation and inhibiting its tetramer-to-dimer transition, which inhibits the Warburg effect and facilitates inflammatory metabolic adaptation in proinflammatory macrophages [46].

Nonhistone lactylation also modulates key proteins involved in inflammatory regulation in macrophages, such as high mobility group protein B1 (HMGB1). HMGB1 is a chromatin-associated nuclear protein that is a key regulatory protein for cell survival [47]. In sepsis, researchers have shown that lactate can drive HMGB1 lactylation in macrophages and that this process is regulated by the p300/CBP pathway, which in turn impairs the nuclear recruitment of p300/CBP via GPR81, ultimately leading to the release of HMGB1 from macrophages via the exosomal pathway, resulting in damage to vascular endothelial integrity [48]. In contrast, in hepatic ischemia‒reperfusion (LI/R), HSPA12A, a novel regulator, can inhibit macrophage chemotaxis and inflammatory activation by inhibiting glycolysis-mediated lactylation and secretion of HMGB1 from hepatocytes, ultimately inhibiting macrophage chemotaxis and inflammatory activation [49].

Regulatory T (Treg) cells play a crucial role in maintaining the immunosuppressive tumor microenvironment. Lactate modulates Treg cell production through MOESIN Lys72 lactylation, thereby improving the interaction of MOESIN with TGF-β receptor I and SMAD3 signaling [50]. In microglia, YY1 lactylation activates FGF2 upregulation to promote angiogenesis, leading to proliferative retinopathy [39].

Different subtypes of CD4 T cells are closely related to immunity, and metabolic reprogramming of OXPHOS and glycolysis can regulate the activation and differentiation of CD4 T cells [51,52]. In autoimmune uveitis, the lacylation of Ikzf1 regulates its binding to TH17-related genes, a process that occurs at lys164 [53]. Lacylation of lys164 directly regulates TH17 related genes, including Runx1, Tlr4, IL-2, and IL-4.

Tumor-infiltrating myeloid cells (TIMs) are key regulators of tumor progression, including monocytes, macrophages, dendritic cells, and neutrophils [54].Researchers found that methyltransferase-like 3 (METTL3) in TIMs can promote Jak1 translation through mode of RNA N6-methyladenosine (m6A), thus activating STAT3 signal transduction. The METTL3/m6A/JAK1/STAT3 axis resulted in enhanced immunosuppressive function of myeloid cells. It is noteworthy that both histone lacylation and non-histone lacylation occur in this process. H3K18 lacylation increased Mettl3 expression in tumor-infiltrating myeloid cells, and Mettl3 lacylation increased the ability to capture m6A modified RNA [55].

These studies highlight the multilevel regulation of nonhistone lactylation in immune cells and provide new molecular mechanisms for immune regulation.

4 Nonhistone lactylation and disease

4.1 Nonhistone lactylation and inflammation

Inflammation is one of the most intensively studied areas of lactylation. During inflammation, high lactate is a sign of poor prognosis [56]. Lactate influences the onset and progression of the inflammatory response by affecting the production of inflammatory mediators, the activation of immune cells and the regulation of inflammatory signaling pathways [57]. In sepsis, lactate inhibits the Warburg effect through activation of PKM2 and promotes the shift of proinflammatory macrophages to a reparative phenotype [46]. In turn, macrophages can take up extracellular lactate via monocarboxylic acid transporter protein (MCT), and secrete HMGB1 lactylation through exosomes to destroy the integrity of endothelial cells and increase vascular permeability [48]. In a subsequent study targeting LI/R, investigators determined that heat shock protein A12A (HSPA12A) protects the liver from LI/R injury by inhibiting macrophage chemotaxis and inflammatory activation through inhibition of glycolysis-mediated lactylation and secretion of HMGB1 from hepatocytes [49]. This provides the basis for targeting lactate/lactate-related signaling to combat sepsis. Furthermore, in sepsis-induced acute kidney injury (SAKI), researchers found that hyperacetylation and inactivation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) enhanced lactate overproduction, which mediated Fis1 lactylation and exacerbated SAKI, whereas lowering lactate levels and lactylation of Fis1 attenuated SAKI [58].

4.2 Nonhistone lactylation and cancer

Lactate is highly expressed in tumor cells and is associated with cancer progression [59]. Nonhistone lactylation has been demonstrated to be associated with key processes involved in tumor metabolism, proliferation, and invasion in gastric, liver, lung, colorectal, and prostate cancers [22,38,[60], [61], [62]]. In HCC, cyclin E2 (CCNE2) lactylation promotes HCC cell growth, and SIRT3 regulates the lactylation of CCNE2 to act as a cancer suppressor [38]. Another study revealed that lactylation of MOESIN Lys72 in HCC cells could be used to regulate Treg cells in the microenvironment and, in this way, enhance downstream TGF-β signaling to counteract anti-PD-1 [50]. In addition, researchers have also found that Glypican-3 can inhibit cancer progression by regulating overall lactylation of HCC cells and c-myc lactylation [63]. In colorectal cancer, hypoxia significantly increased the protein level and the level of lactylated β-catenin in CRC cells, and knockdown of this protein significantly inhibited the growth and stemness of CRC cells [64]. In prostate cancer, hypoxia-inducible factor 1a (HIF-1a) lactylation promotes the transcription of KIAA (ahyaluronic acid binding protein), which in turn promotes angiogenesis [40]. In gastric cancer, researchers have shown that METTL16 lactylation is associated with copper-induced death due to high copper concentrations. Copper stress promotes METTL16 lactylation at K229, followed by cuproptosis. Elevated levels of METTL16 significantly improved the therapeutic efficacy of the copper ionophore elesclomol, which, in combination with the SIRT2 inhibitor AGK2, induces cuproptosis in gastric cancer cells both in vitro and in vivo, thus providing a novel approach for the treatment of gastric cance [61]. In cervical cancer, emulsification of CUB and LCCL structural domain-containing type I (DCBLD1) maintains DCBLD1 stability through a mechanism involving increased enrichment of HIF-1 in the DCBLD1 promoter region. Ultimately, it activates the pentose phosphate pathway (PPP) by inhibiting the autophagic degradation of G6PD, thereby promoting cancer progression [65].These studies suggest that lactylation is deeply involved in key protein modifications in tumors, thus impacting tumor development, and studies targeting lactylation can aid in tumor therapy.

4.3 Nonhistone lactylation and neurological disorders

Lactate, a metabolic substance, is a source of energy for neurons and is responsible for regulating neuronal signaling functions and promoting nervous system stability [66]. Altered levels of lactate and lactylation have been shown to potentially be associated with social stress and stress-related neuroexcitation [23]. Lymphocyte cytoplasmic protein 1 (LCP1), a major cytoskeletal binding protein associated with the control of cell motility, is thought to be associated with LI/R [67,68]. Researchers have shown that LCP1 lactylation promotes the progression of cerebral infarction, and the glycolysis inhibitor 2-DG may help reduce the level of LCP1 lactylation and induce cellular damage [67].

4.4 Nonhistone lactylation and diseases of the cardiovascular system

Lactate is an important energy support for cardiac metabolism. Lactate is associated with cardiovascular system diseases such as cardiac hypertrophy, myocardial injury, heart failure, and atherosclerosis[[69], [70], [71], [72]]. Using a high-fat diet-induced apolipoprotein-deficient mouse model of ASCVD, researchers found that an exercise-induced increase in lactylation promotes Mecp2 K271 lactylation, which inhibits the expression of Eregs, leading to alterations in the downstream MAPK pathway, resulting in the inhibition of atherosclerosis progression [69]. In heart failure, the sarcomeric interaction of a-MHC with Titin is critical for cardiac structure and contraction. Zhang et al. reported that a-MHC K1897 lactylation directly modulates the interaction between a-MHC and Tinin, thereby alleviating heart failure [70]. In myocardial infarction, lactylation in turn induces cardiac fibrosis and exacerbates cardiac dysfunction, which results from increased Snail1 lactylation, and Snail lactylation induction leads to endothelial mesenchymal transition (EndoMT) and TGF-β/Smad2 activation [71]. These studies demonstrate the complex role of lactate in the cardiovascular system.

4.5 Nonhistone lactylation and other diseases

In nonalcoholic fatty liver disease, researchers have shown that fatty acid synthase K673 lactylation leads to a decrease in enzyme activity in the regulation of hepatic lipids by MPC1, which mediates hepatic lipid synthesis via MPC1 [73]. In addition to disease, Mao et al. reported that exercise-induced intracellular hypoxia induced lactylation and that PDHA1 and CPT2 lactylation could limit OXPHOS to balance the duration of fatigue during high-intensity endurance exercise [30].The currently known regulation of nonhistone lactylation in cell lines and diseases is shown in Table 2.

5 Lacylation and other modifications

Lacylation and acetylation are types of post-translational modifications on lysine. Zhang et al. employed M1 macrophages to demonstrate that histone lacylation and acetylation exhibit distinct temporal dynamics [9]. Nevertheless, there exists an interaction between acetylation and lacylation in diseases. In sepsis, lactic acid promotes the lacylation and acetylation of HMGB1, thereby enhancing endothelial permeability [48]. In acute kidney injury, excessive lactate mediated by PDHA1 acetylation can increase the lacylation of Fis1 and ultimately exacerbate the progression of the disease [58].

M6A modification is the most abundant RNA modification in eukaryotic cells and plays a pivotal role in tumorigenesis [76]. The METTL family represens a category of proteins that transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules [77]. In gastric cancer, METTL16 lacylation promotes m6A modification on FDX1 mRNA, ultimately facilitating cuproptosis. In colon tumors, METTL3 lacylation promotes m6A modification on Jak1 mRNA, promoting the immunosuppression of tumor-infiltrating myeloid cells [55,61]. Additionally, by seeking different lacylation-related genes between normal tissues and tumor tissues, researchers identified the genes related to m6A through correlation analysis and ultimately successfully constructed a risk model associated with clear cell renal cell carcinoma [78].

Nevertheless, further studies are required on the connection between lacylation and methylation, acetylation or other modifications.

6 Drug development and therapeutic potential

Cellular metabolic programming in cancer is regulated by a variety of oncogenes, such as HIF-1, Myc, p53, and the PI3K/Akt/mTOR pathway [79,80]. The efficacy of cancer therapy can be improved by the use of glycolysis inhibitors or the combination of glycolysis inhibitors and other drugs [81]. Currently, inhibition of the glycolytic enzymes hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and glucose transporter protein (GLUT) has been shown to inhibit tumors [82]. In addition to the above therapeutic targets, therapeutic modalities targeting lactylation transporter proteins or lactylated writing or erasing proteins, such as MCT1, MCT4, P300/CBP, and the sirtuin (SIRT) family, have also shown tumor potential [27,83].

LDH is a key enzyme that catalyzes the final step of glycolysis, converting pyruvate to lactate. LDH expression is elevated in a variety of malignant tumors, is associated with the prognosis of liver, lung, and pancreatic cancers, and is considered to be a potent target for targeted cancer therapies[[84], [85], [86], [87], [88]]. Oxamic acid sodium (OXA), a well-defined inhibitor of LDHA, can reduce lactylation levels. Decreased cell migration in esophageal cancer; increased cytotoxic effects on docetaxel; induced apoptosis in prostate cancer; and increased the sensitivity of colon cancer cells to cisplatin, olaparib or etoposide [60,89,90].2 Deoxy-D-glucose (2-DG) is an inhibitor of glucose metabolism that induces apoptosis by inhibiting the functions of hexokinase and glucose-6-phosphate isomerase [91]. 2-DG inhibits the glycolytic pathway, inhibiting the generation of a variety of malignant tumors[[92], [93], [94]]. 2-DG has been subjected to phase I clinical trials [95]. In myocardial infarction, 2-DG has also been shown to reduce lactate levels, thereby alleviating myocardial infarction [71].

The transmembrane transport of lactate is controlled by a family of MCTs, particularly MCT1 and MCT4, which are important factors in tumor invasion through the transport of lactate [83]. α-Cyano-4-hydroxycinnamate (α CHC), an inhibitor of MCT1/2 that inhibits the ability of lactate to be transported, can regulate lactate content [96]. CHC has been shown to be involved in the treatment of dry breast, pancreatic, and gastric cancers[[97], [98], [99]]. Fan et al. reported that α CHC could be used to attenuate lactate-induced cardiac insufficiency and EndoMT after MI in a study of myocardial infarction [71]. The SIRT family has also been shown to undergo delactylation. AGK2, a selective SIRT2 inhibitor, has been shown in ex vivo assays to increase the sensitivity of gastric cancers, particularly in mucinous adenocarcinomas, to elesclomol [61]. Honokiol, a naturally occurring agent and activator of SIRT3, was shown to increase the sensitivity of gastric cancers, particularly in mucinous adenocarcinomas, to Elesclomol by investigators who determined that Honokiol increased SIRT3 expression in a dose-dependent manner, leading to a decrease in lactylation levels, and this process was shown to reduce HCC growth and promote apoptosis in HCC cells in ex vivo assays [38].

In addition to the therapeutic use of lactylation proteins as targets of action, analysis of the lactylation profile of tumors through datasets can be used to determine the therapeutic efficacy and prognosis of tumors [100]. For example, lactylation-related models of gastric cancer can be constructed to identify individual tumors with different immune evasion risks [100]. Similarly, the construction of lactylation models for hepatocellular carcinoma and breast cancer renal cancer has successfully predicted the effect of drugs on tumor response and prognosis78,[101], [102], [103], [104], [105].Drugs that target lactic acid production and transport are summarized in Table 3.Table 3 Drugs that target the production and transport of lactate.

Table 3Drug	Type	Effect	
AGK2	SIRT2 inhibitor	effectively inhibit gastric cancer progression With Elesclomol	
Honokiol	SIRT3 activator	Induction of apoptosis in HCC cells	
C646	P300/CBP inhibitor	Attenuated levels of lactate-promoted lactylation in macrophages	
2-DG	HK inhibitor	Reduction of lactate-induced cardiac insufficiency and EndoMT after MI	
Oxamic acid sodium	LDHA inhibitor	Increased sensitivity of HCT116 and RKO colon cancer cells to cisplatin, olaparib, or etoposide	
α-cyano-4-hydroxycinnamate	MCT1/2 inhibitor	Reduction of lactate-induced cardiac insufficiency and EndoMT after MI	
GSK2837808A	LDHA inhibitor	Decrease SAKI	

7 Conclusions and perspectives

Lactylation is involved in a variety of biological processes, including gene expression regulation, cell signaling, and inflammatory responses, which have a significant impact on disease occurrence and progression [106]. Specifically, in the field of oncology, lactate is involved in key processes such as tumor cell proliferation, metastasis, and drug resistance by modifying key proteins [107]. On the one hand, lactylation can regulate metabolic reprogramming within tumor cells, enabling tumor cells to adapt to harsh microenvironments and maintain their survival and proliferation advantages [18]. On the other hand, lactylation can also affect the acid‒base balance of EMT and promote acidification of the tumor microenvironment, thereby promoting tumor cell invasion and metastasis [108,109]. In addition, proteins involved in lactylation can act as immunomodulators and participate in the regulation of signal transduction pathways in tumor cells [110]. Lactylation mediates TGF-β, Hippo, MAPK and other pathways that affect tumor cell proliferation and survival signaling [50,100,111,112]. In neurological disorders, lactate, a metabolite, not only is a source of energy for neurons in the nervous system but also participates in the regulation of neuronal signaling functions and promotes the stability of the nervous system [113,114]. In the cardiovascular system, nonhistone lactylation has been found to be closely associated with the onset and progression of cardiovascular diseases such as atherosclerosis, myocardial infarction, and heart failure. This form of modification is involved in physiological processes such as the regulation of vascular endothelial cell function, the modulation of inflammatory responses in the vascular wall, and vasoconstriction and dilation, which have important implications for cardiovascular health [115,116]. Moreover, nonhistone lactylation is also widely involved in the inflammatory process, participating in key steps such as the production of inflammatory mediators, the activation of immune cells, and the regulation of inflammatory signaling pathways [46,48]. Further studies have shown that the regulation of targets in the lactate metabolic pathway, such as MCT, GLUT, LDH, and SIRT, may positively affect the treatment of related diseases [27]. The prediction of the characteristics of lactylation-related genes can help to identify potential targets for tumor therapy [117].

In summary, there is a close relationship between nonhistone lactylation and diseases, and in-depth study of the mechanism of action of this form of modification is highly important for revealing the pathogenesis of diseases, understanding the progression of diseases, and developing new therapeutic approaches.

Funding

This research received no external funding.

Institutional review board statement

Not applicable.

Informed consent statement

Not applicable.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Contributions

(I) Conception and design: Y Yao; (II) Administrative support: None (III); Collection and assembly of data: H Yu, T Zhu; (V) Data analysis and interpretation: D. Ma; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

CRediT authorship contribution statement

Hao Yu: Writing – review & editing, Writing – original draft. Tingting Zhu: Writing – original draft. Dongwen Ma: Data curation. Xiaohan Cheng: Resources. Shengjia Wang: Formal analysis. Yongzhong Yao: Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

The following abbreviations are used in this manuscript:

PTM	Posttranslational modification	
Kla	Lysine lactylation	
OXPHOS	Oxidative phosphorylation	
PPP	Pentose phosphate pathway	
HR	Homologous recombination	
HCC	Hepatocellular carcinoma	
AIS	Acute ischemic stroke	
LGSH	Lactoyl glutathione	
CIRI	Cerebral ischemia/reperfusion injury	
NADH	Nicotinamide adenine dinucleotide	
ATP	Adenosine triphosphate	
Arg1	Arginase 1	
YTHDF2	YTH N6-Methyladenosine RNA Binding Protein F2	
GLO2	Glyoxalase 2	
CPT2	Carnitine palmitoyltransferase 2	
AlaRS	Alanyl-tRNA synthetase	
cAMP	Cyclic adenosine monophosphate	
GPR81	G protein-coupled receptor 81	
CTSD	Cathepsin D	
PKM2	Pyruvate kinase M2	
CCNE2	Cyclin E2	
SIRT	Sirtuin	
HIF-1a	Hypoxia-inducible factor 1a	
HMGB1	High mobility group protein B1	
LI/R	Ischemia‒reperfusion	
TGF-β	Transforming growth factor	
SMAD3	Mothers against decapentaplegic homolog 3	
Treg	Regulatory T	
MCT	Monocarboxylic acid transporter protein	
HSPA12A	Heat shock protein A12A	
SAKI	Sepsis-induced acute kidney injury	
PDHA1	Pyruvate Dehydrogenase E1 Subunit Alpha 1	
Mecp2	Methyl-CpG Binding Protein 2	
Fis1	Fission, Mitochondrial 1	
Snail1	Snail Family Transcriptional Repressor 1	
FASN	Fatty acid synthase	
Vps34	Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3Vps34	
METTL3	Methyltransferase 3, N6-Adenosine-Methyltransferase Complex Catalytic Subunit	
PFKP	Phosphofructokinase, Platelet	
CCNE2	Cyclin E2	
CPT2	Carnitine Palmitoyltransferase 2	
IDH3G	Isocitrate Dehydrogenase (NAD(+)) 3 Non-Catalytic Subunit Gamma	
LCP1	Lymphocyte Cytosolic Protein 1	
DCBLD1	Discoidin, CUB And LCCL Domain Containing 1	
Ikzf1	IKAROS Family Zinc Finger 1	
TIM	Tumor-infiltrating myeloid cells	
m6A	N6-methyladenosine	

Acknowledgments

All the figures in the manuscript were drawn in Figdraw.
==== Refs
References

1 Li X. Yang Y. Zhang B. Lactate metabolism in human health and disease Signal Transduct. Targeted Ther. 7 1 2022 305
2 Brooks G.A. Lactate as a fulcrum of metabolism Redox Biol. 35 2020 101454
3 Faubert B. Li K.Y. Cai L. Lactate metabolism in human lung tumors Cell 171 2 2017 358 371.e9 28985563
4 Liao Z.-X. Kempson I.M. Hsieh C.-C. Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer Drug Discov. Today 26 11 2021 2508 2514 34325010
5 Colegio O.R. Chu N.-Q. Szabo A.L. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid Nature 513 7519 2014 559 563 25043024
6 Liu W. Wang Y. Bozi L.H.M. Lactate regulates cell cycle by remodeling the anaphase promoting complex Nature 2023
7 Sun W, Jia M, Feng Y, et al. Lactate is a bridge linking glycolysis and autophagy through lactylation[J]. Autophagy, , 19(12): 3240–3241.
8 D N. T L. H W. Lactic acid in tumor invasion Clinica chimica acta; international journal of clinical chemistry, Clin Chim Acta 2021 522
9 Zhang D. Tang Z. Huang H. Metabolic regulation of gene expression by histone lactylation Nature 574 7779 2019 575 580 31645732
10 Pan R.-Y. He L. Zhang J. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease Cell Metabol. 34 4 2022 634 648.e6
11 Chu X. Di C. Chang P. Lactylated histone H3K18 as a potential biomarker for the diagnosis and predicting the severity of septic shock Front. Immunol. 12 2022 786666
12 Yu J. Chai P. Xie M. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma Genome Biol. 22 2021 85 33726814
13 Gao M. Zhang N. Liang W. Systematic analysis of lysine lactylation in the plant fungal pathogen botrytis cinerea Front. Microbiol. 11 2020 594743
14 Wan N. Wang N. Yu S. Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome Nat. Methods 19 7 2022 854 864 35761067
15 Yang Z. Yan C. Ma J. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma Nat. Metab. 2023
16 Wang J.-H. Mao L. Wang J. Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination Cell. Oncol. 46 3 2023 465 480
17 Warburg O. On the origin of cancer cells Science, American Association for the Advancement of Science 123 3191 1956 309 314
18 Chen A.-N. Luo Y. Yang Y.-H. Lactylation, a novel metabolic reprogramming code: current status and prospects Front. Immunol. 12 2021 688910
19 Zhang N. Jiang N. Yu L. Protein lactylation critically regulates energy metabolism in the Protozoan parasite trypanosoma brucei Front. Cell Dev. Biol. 9 2021 719720
20 Meng X. Baine J.M. Yan T. Comprehensive analysis of lysine lactylation in rice (oryza sativa) grains J. Agric. Food Chem. 69 29 2021 8287 8297 34264677
21 Yao Y. Bade R. Li G. Global-scale profiling of differential expressed lysine-lactylated proteins in the cerebral endothelium of cerebral ischemia-reperfusion injury rats Cell. Mol. Neurobiol. 43 5 2023 1989 2004 36030297
22 Cheng Z. Huang H. Li M. Proteomic analysis identifies PFKP lactylation in SW480 colon cancer cells iScience 27 1 2024 108645
23 Hagihara H. Shoji H. Otabi H. Protein lactylation induced by neural excitation Cell Rep. 37 2 2021 109820
24 Yang Y.-H. Wang Q.-C. Kong J. Global profiling of lysine lactylation in human lungs Proteomics 23 15 2023 2200437
25 Ye L. Jiang Y. Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation Cytokine Growth Factor Rev. 68 2022 81 92 36376165
26 Rabinowitz J.D. Enerbäck S. Lactate: the ugly duckling of energy metabolism Nature Metabolism, Nature Publishing Group 2 7 2020 566 571
27 Chen L. Huang L. Gu Y. Lactate-lactylation hands between metabolic reprogramming and immunosuppression International Journal of Molecular Sciences, Multidisciplinary Digital Publishing Institute 23 19 2022 11943
28 Hui S. Ghergurovich J.M. Morscher R.J. Glucose feeds the TCA cycle via circulating lactate Nature, Nature Publishing Group 551 7678 2017 115 118
29 Do G. Eq J. Cc A. Non-enzymatic lysine lactoylation of glycolytic enzymes[J]. Cell chemical biology Cell Chem. Biol. 27 2 2020
30 Mao Y. Zhang J. Zhou Q. Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation Cell Res. 34 1 2024 13 30 38163844
31 Brown T.P. Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon Pharmacol. Therapeut. 206 2020 107451
32 Yang L. Gilbertsen A. Xia H. Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway JCI insight 8 4 2023 e163820
33 Ishihara S. Hata K. Hirose K. The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer Sci. Rep. 12 2022 6261 35428832
34 Yang K. Fan M. Wang X. Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis Sci. Adv. 8 17 2022 eabm8965
35 Guo S. Zhou J. Lou P. Potentiated effects of lactate receptor GPR81 on immune microenvironment in breast cancer Mol. Carcinog. 62 9 2023 1369 1377 37249360
36 Yang K. Xu J. Fan M. 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
37 Laroche S. Stil A. Germain P. Participation of L-lactate and its receptor HCAR1/GPR81 in neurovisual development Cells 10 7 2021 1640 34208876
38 Jin J. Bai L. Wang D. SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth EMBO Rep. 2023
39 Wang X. Fan W. Li N. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 Genome Biol. 24 1 2023 87 37085894
40 Luo Y. Yang Z. Yu Y. HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer Int. J. Biol. Macromol. 222 Pt B 2022 2225 2243 36209908
41 Kumagai S. Koyama S. Itahashi K. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments Cancer Cell, Elsevier 40 2 2022 201 218.e9
42 Sanmarco L.M. Rone J.M. Polonio C.M. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells Nature 620 7975 2023 881 889 37558878
43 Irizarry-Caro R.A. McDaniel M.M. Overcast G.R. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation Proc. Natl. Acad. Sci. U.S.A. 117 48 2020 30628 30638 33199625
44 Hou P. Luo L. Chen H. Ectosomal PKM2 promotes HCC by inducing macrophage differentiation and remodeling the tumor microenvironment Molecular Cell, Elsevier 78 6 2020 1192 1206.e10
45 Xie M. Yu Y. Kang R. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation Nat. Commun. 7 2016 13280
46 Wang J. Yang P. Yu T. Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages Int. J. Biol. Sci. 18 16 2022 6210 6225 36439872
47 Tang D. Kang R. Zeh H.J. The multifunctional protein HMGB1: 50 years of discovery Nature Reviews Immunology, Nature Publishing Group 23 12 2023 824 841
48 Yang K. Fan M. Wang X. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis Cell Death Differ. 29 1 2022 133 146 34363018
49 Du S. Zhang X. Jia Y. Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes Theranostics 13 11 2023 3856 3871 37441587
50 Gu J. Zhou J. Chen Q. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells Cell Reports, Elsevier 40 3 2022
51 Angiari S. Runtsch M.C. Sutton C.E. Pharmacological activation of pyruvate kinase M2 inhibits CD4+ T cell pathogenicity and suppresses autoimmunity Cell Metabol. 31 2 2020 391 405.e8
52 Pucino V. Certo M. Bulusu V. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring Cell Metabol. 30 6 2019 1055 1074.e8
53 Fan W. Wang X. Zeng S. Global lactylome reveals lactylation-dependent mechanisms underlying TH17 differentiation in experimental autoimmune uveitis Sci. Adv. 9 42 2023 eadh4655
54 Cheng S. Li Z. Gao R. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells Cell 184 3 2021 792 809.e23 33545035
55 Xiong J. He J. Zhu J. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells Mol. Cell 82 9 2022 1660 1677.e10 35320754
56 Nguyen H.B. Rivers E.P. Knoblich B.P. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock Crit. Care Med. 32 8 2004 1637 1642 15286537
57 Certo M. Llibre A. Lee W. Understanding lactate sensing and signalling Trends in Endocrinology & Metabolism, Elsevier 33 10 2022 722 735
58 An S. Yao Y. Hu H. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation Cell Death Dis. 14 7 2023 457 37479690
59 Doherty J.R. Cleveland J.L. Targeting lactate metabolism for cancer therapeutics J. Clin. Investig. 123 9 2013 3685 3692 23999443
60 Chen Y. Wu J. Zhai L. Metabolic regulation of homologous recombination repair by MRE11 lactylation Cell 2023
61 Sun L. Zhang Y. Yang B. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer Nat. Commun. 14 1 2023 6523 37863889
62 Wang M. He T. Meng D. BZW2 modulates lung adenocarcinoma progression through glycolysis-mediated IDH3G lactylation modification J. Proteome Res. 22 12 2023 3854 3865 37955350
63 Yao G. Yang Z. Glypican-3 knockdown inhibits the cell growth, stemness, and glycolysis development of hepatocellular carcinoma cells under hypoxic microenvironment through lactylation Archives of Physiology and Biochemistry, Taylor & Francis 0 0 2023 1 9
64 Miao Z. Zhao X. Liu X. Hypoxia induced β-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway Exp. Cell Res. 422 1 2023 113439
65 Meng Q. Sun H. Zhang Y. Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression J. Exp. Clin. Cancer Res.: CRN 43 1 2024 36
66 Magistretti P.J. Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule Nat. Rev. Neurosci. 19 4 2018 235 249 29515192
67 Zhang W. Xu L. Yu Z. Inhibition of the glycolysis prevents the cerebral infarction progression through decreasing the lactylation levels of LCP1 Mol. Biotechnol. 65 8 2023 1336 1345 36574182
68 Wen M. Jin Y. Zhang H. Proteomic analysis of rat cerebral cortex in the subacute to long-term phases of focal cerebral ischemia-reperfusion injury J. Proteome Res. 18 8 2019 3099 3118 31265301
69 Wang Y. Chen L. Zhang M. Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway Atherosclerosis, Elsevier 375 2023 45 58
70 Zhang N. Zhang Y. Xu J. α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure Cell Research, Nature Publishing Group 33 9 2023 679 698
71 Fan M, Yang K, Wang X, et al. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction[J]. Sci. Adv., , 9(5): eadc9465.
72 Dai C. Li Q. May H.I. Lactate dehydrogenase A governs cardiac hypertrophic growth in response to hemodynamic stress Cell Rep. 32 9 2020 108087
73 Gao R. Li Y. Xu Z. Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease Hepatology (Baltimore, Md 78 6 2023 1800 1815
74 Jia M. Yue X. Sun W. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation Sci. Adv. 9 22 2023 eadg4993
75 Yu Y. Huang X. Liang C. Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer Eur. J. Pharmacol. 957 2023 176007
76 Wang Y. Wang Y. Patel H. Epigenetic modification of m6A regulator proteins in cancer Mol. Cancer 22 1 2023 102 37391814
77 Campeanu I.J. Jiang Y. Liu L. Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer Scientific Reports, Nature Publishing Group 11 1 2021 14784
78 Yang L. Wang X. Liu J. Prognostic and tumor microenvironmental feature of clear cell renal cell carcinoma revealed by m6A and lactylation modification-related genes Front. Immunol. 14 2023 1225023
79 Abdel-Wahab A.F. Mahmoud W. Al-Harizy R.M. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy Pharmacol. Res. 150 2019 104511
80 Vaupel P. Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding J. Physiol. 599 6 2021 1745 1757 33347611
81 Feng J. Li J. Wu L. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma J. Exp. Clin. Cancer Res.: CRN 39 1 2020 126
82 Chelakkot C. Chelakkot V.S. Shin Y. Modulating glycolysis to improve cancer therapy Int. J. Mol. Sci. 24 3 2023 2606 36768924
83 Payen V.L. Mina E. Van Hée V.F. Monocarboxylate transporters in cancer Mol. Metabol. 33 2020 48 66
84 Mezquita L. Auclin E. Ferrara R. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer JAMA Oncol. 4 3 2018 351 357 29327044
85 Comandatore A. Franczak M. Smolenski R.T. Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers Semin. Cancer Biol. 86 Pt 2 2022 93 100 36096316
86 Claps G. Faouzi S. Quidville V. The multiple roles of LDH in cancer Nat. Rev. Clin. Oncol. 19 12 2022 749 762 36207413
87 Raj S. Kumar A. Kumar D. Regulation of glycolysis in head and neck cancer Adv. Exp. Med. Biol. 1280 2021 219 230 33791985
88 Lei Y. Han P. Chen Y. Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A Clin. Transl. Med. 12 1 2022 e686 35090076
89 Muramatsu H. Sumitomo M. Morinaga S. Targeting lactate dehydrogenase-A promotes docetaxel-induced cytotoxicity predominantly in castration-resistant prostate cancer cells Oncol. Rep. 42 1 2019 224 230 31180564
90 Forkasiewicz A. Stach W. Wierzbicki J. Effect of LDHA inhibition on TNF-α-induced cell migration in esophageal cancers Int. J. Mol. Sci. 23 24 2022 16062
91 Pajak B. Siwiak E. Sołtyka M. 2-Deoxy-d-Glucose and its analogs: from diagnostic to therapeutic agents Int. J. Mol. Sci. 21 1 2019 234 31905745
92 Singh S. Pandey S. Chawla A.S. Dietary 2-deoxy-D-glucose impairs tumour growth and metastasis by inhibiting angiogenesis Eur. J. Cancer 123 2019 11 24 31670076
93 Su M. Shan S. Gao Y. 2-Deoxy-D-glucose simultaneously targets glycolysis and Wnt/β-catenin signaling to inhibit cervical cancer progression IUBMB Life 75 7 2023 609 623 36809563
94 Zhang T. Zhu X. Wu H. Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: combined administration of Polydatin and 2-Deoxy-d-glucose J. Cell Mol. Med. 23 5 2019 3711 3723 30920152
95 Raez L.E. Papadopoulos K. Ricart A.D. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors Cancer Chemother. Pharmacol. 71 2 2013 523 530 23228990
96 McKenna M.C. Hopkins I.B. Carey A. Alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons J. Neurosci. Res. 66 5 2001 747 754 11746398
97 Guan X. Morris M.E. In vitro and in vivo efficacy of AZD3965 and alpha-cyano-4-hydroxycinnamic acid in the murine 4T1 breast tumor model AAPS J. 22 4 2020 84 32529599
98 Kumar A. Kant S. Singh S.M. Targeting monocarboxylate transporter by α-cyano-4-hydroxycinnamate modulates apoptosis and cisplatin resistance of Colo205 cells: implication of altered cell survival regulation Apoptosis: An International Journal on Programmed Cell Death 18 12 2013 1574 1585 23955790
99 Schönrogge M. Kerndl H. Zhang X. α-cyano-4-hydroxycinnamate impairs pancreatic cancer cells by stimulating the p38 signaling pathway Cell. Signal. 47 2018 101 108 29609037
100 Yang H. Zou X. Yang S. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer Front. Immunol. 14 2023 1149989
101 Jiao Y. Ji F. Hou L. Lactylation-related gene signature for prognostic prediction and immune infiltration analysis in breast cancer Heliyon, Elsevier 10 3 2024 e24777
102 Cheng Z. Huang H. Li M. Lactylation-related gene signature effectively predicts prognosis and treatment responsiveness in hepatocellular carcinoma Pharmaceuticals 16 5 2023 644 37242427
103 Cai D. Yuan X. Cai D.Q. Integrative analysis of lactylation-related genes and establishment of a novel prognostic signature for hepatocellular carcinoma J. Cancer Res. Clin. Oncol. 149 13 2023 11517 11530 37400571
104 Deng J. Liao X. Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer BMC Med. Genom. 16 2023 283
105 Wu Q. Li X. Long M. Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma Sci. Rep. 13 1 2023 18642
106 Lv X. Lv Y. Dai X. Lactate, histone lactylation and cancer hallmarks Expet Rev. Mol. Med. 25 2023 e7
107 Wang N. Wang W. Wang X. Histone lactylation boosts reparative gene activation post-myocardial infarction Circ. Res. 131 11 2022 893 908 36268709
108 Wang T. Ye Z. Li Z. Lactate-induced protein lactylation: a bridge between epigenetics and metabolic reprogramming in cancer Cell Prolif. 56 10 2023 e13478
109 Qu J. Li P. Sun Z. Histone lactylation regulates cancer progression by reshaping the tumor microenvironment Front. Immunol. 14 2023 1284344
110 Fang X. Zhao P. Gao S. Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism Int. J. Biol. Macromol. 237 2023 123810
111 Izzo L.T. Wellen K.E. Histone lactylation links metabolism and gene regulation Nature 574 7779 2019 492 493 31645737
112 Xie B. Lin J. Chen X. CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer Mol. Cancer 22 1 2023 151 37684641
113 Zhou Y. Yang L. Liu X. Lactylation may be a novel posttranslational modification in inflammation in neonatal hypoxic-ischemic encephalopathy Front. Pharmacol. 13 2022 926802
114 Yao X. Li C. Lactate dehydrogenase A mediated histone lactylation induced the pyroptosis through targeting HMGB1 Metab. Brain Dis. 38 5 2023 1543 1553 36870018
115 Ouyang J. Wang H. Huang J. The role of lactate in cardiovascular diseases Cell Commun. Signal.: CCS 21 1 2023 317 37924124
116 Yi L. Tang D. Xiang X. New mechanisms: from lactate to lactylation to rescue heart failure Bioscience Trends 2024
117 Sun Z. Song Y. Li J. Potential biomarker for diagnosis and therapy of sepsis: lactylation Immunity, Inflammation and Disease 11 10 2023 e1042
