Exploring lactylation and cancer biology: insights from pathogenesis to clinical applications

Abstract

As a byproduct of glycolysis, lactate functions as a signaling molecule, a substrate for energy metabolism, and a regulator of the tumor microenvironment (TME). It is involved in various biological processes, including energy shuttling, tumor growth and invasion, drug resistance, and immune evasion. Lactylation, a recently identified post-translational modification (PTM), acts as a bridge between gene regulation and cellular metabolism, thus playing a crucial role in tumor biology. Similar to other epigenetic modifications, lactylation influences the spatial conformation of chromatin, modulates DNA accessibility, and regulates gene expression. It intricately participates in TME-related processes by orchestrating immune state transitions and enhancing the malignant characteristics of tumors. This review summarizes lactylation-related genes in tumors, the role of lactylation in the TME, the interactions of the genes with other metabolic pathways, and the potential mechanisms underlying tumor progression as well as their clinical implications. Despite its nascent stage, research on the epigenetic regulation of tumor-related genes by lactylation holds promise. In this review, we highlighted unresolved challenges in this field and provided insights that may guide the development of novel targeted therapies for cancer.

1 Introduction

Glycolysis is a pathway of glucose breakdown that enables cells to generate energy under both normoxic and hypoxic conditions. In the tumor microenvironment (TME), glycolysis is remarkably active in cancer cells, even under high-oxygen concentrations. In the 1920s, Warburg et al. identified the characteristic “aerobic glycolysis” in tumors, now known as the Warburg effect (Warburg et al., 1927). Compared with surrounding tissues, tumors consume larger amounts of glucose. Through glycolysis, tumor cells generate adenosine triphosphate (ATP) and produce excessive lactate intracellularly, even in the presence of sufficient oxygen. Lactate, an oxidizable substrate, subsequently generates a substantial amount of ATP to promote cancer cell proliferation. Despite its lower efficiency than mitochondrial oxidative phosphorylation (OXPHOS), glycolysis-dependent ATP production allows tumor cells to obtain abundant metabolic intermediates. These intermediates are essential for synthesizing lipids, nucleotides, and other biomolecules required for tumor growth. In addition to energy production, glycolysis-derived lactate drives acidification of the extracellular matrix, impairing immune cell function (Li et al., 2022) and promoting tumor metastasis and invasion (Jiang et al., 2020). Lactate is transported between cells via monocarboxylate transporters (MCTs), particularly MCT1 (Brooks, 2018; Carneiro et al., 2017), or acts as a signaling molecule through specific receptors (Roland et al., 2014).

In 2019, Zhang et al. discovered that lactate could regulate gene expression by inducing histone lactylation, a process now termed lactylation (Zhang et al., 2019). Lactylation is a lactate-mediated post-translational modification (PTM) similar to phosphorylation, acetylation, methylation, and ubiquitination. Lactate-driven epigenetic alterations represent a critical link through which metabolic states influence gene expression. Increased levels of histone and non-histone lactylation have been observed in various malignancies and are closely associated with epigenetic dysregulation and metabolic dysfunction. These processes collectively regulate intracellular signaling, gene expression, and protein functionality (Chen H. et al., 2024; Zong et al., 2024; Chen et al., 2024b). Despite its significance, the mechanisms and functions of lactylation remain unclear. An in-depth understanding of the role of this novel epigenetic modification in tumor progression may provide insights into the molecular mechanisms underlying metabolic reprogramming in cancer and facilitate the development of therapeutic strategies targeting metabolism. This review provides a comprehensive overview of the research progress of lactylation in tumors.

2 Histone and non-histone lactylation in the TME

The TME comprises tumor cells, cancer-associated fibroblasts (CAFs), and tumor-associated immune cells, some of which are regulated by lactate (Han et al., 2023).

Both normoxic and hypoxic cellular populations are found in the TME. Hypoxic cells, inherently lacking the ability to oxidize lactate, are typically located in regions with the highest lactate levels. These cells rely on glucose for Warburg-like metabolism, generating a large amount of lactate, which is subsequently transported to adjacent oxygenated cells via MCT1. A metabolic symbiosis has been observed between normoxic and hypoxic cells, wherein some cells undergo Warburg-like metabolism, whereas others metabolize lactate through OXPHOS-dependent pathways (Hui et al., 2017; Faubert et al., 2017). This lactate shuttling facilitates the redistribution and efficient utilization of energy substrates, which are used by tumor cells to optimize energy production and meet the demands of rapid proliferation. This division of labor in energy metabolism serves as a crucial factor contributing to the formation of a TME (Brooks, 2018; Brooks, 2020). Over the past 5 years, studies have suggested that lactylation plays an essential role in shaping many pro-tumor characteristics of cells within the TME. In addition, lactylation serves as an important epigenetic mechanism in the TME (Jiao et al., 2024; Xiong et al., 2022). High lactate levels suppress immune cells and contribute to lactylation (Apostolova and Pearce, 2022; Elia et al., 2022) on both histone and non-histone proteins. This section systematically discusses the roles of histone and non-histone lactylation in the TME, providing a valuable reference for investigating how the TME is shaped by epigenetics.

2.1 Histone lactylation

Histones are proteins that form the core of nucleosomes wrapped by DNA, serving as the primary structural proteins of chromosomes. PTM of histones can regulate DNA replication, transcription, and repair by altering nucleosome interactions or recruiting non-histone proteins, which are essential for maintaining homeostasis (Millan-Zambrano et al., 2022). With the advancement of high-sensitivity mass spectrometry techniques in epigenetic research, the diversity of histone PTMs continues to expand (Sabari et al., 2017). Lysine acylation of histones is a common type of PTM, with hydrophobicity, charge, and hydrocarbon chain length being different across various acylation types (Hirschey and Zhao, 2015). This modification is regulated by specific enzymes that act as “writers” and “erasers”. For instance, histone acetyltransferase (HAT) p300 is a key “writer” of histone acetylation (Moreno-Yruela et al., 2022a), whereas histone deacetylases (HDACs) remove acetyl groups from the lysine residues of both histone and non-histone proteins. Effector proteins, termed “readers,” specifically interpret modified gene information and regulate downstream signaling pathways, contributing to the dynamic regulation of lysine acylation (Moreno-Yruela et al., 2022b; Rothbart et al., 2015).

Lysine lactylation (Kla) is a novel type of PTM that directly stimulates gene transcription (Zhang et al., 2019) (Figure 1). Zhao et al. detected a 72.021-Da mass shift at the lysine residues of histones in human tumor cells using tandem mass spectrometry (MS/MS) in conjunction with high-performance liquid chromatography (HPLC). This mass shift was hypothesized to result from the addition of a lactyl group to lysine residues, which validated lactate as a substrate for histone modification and established histone lactylation as a PTM in vivo (Zhang et al., 2019; Huang et al., 2014). Lactyl-CoA donates a lactyl group to lysine residues on histone tails via p300 (Zeng et al., 2023). HBO1, a HAT belonging to the MYST family, has been identified as another lactyltransferase mediating histone lactylation-dependent gene transcription (Niu et al., 2024). In addition, HDAC1–3 have been identified as “erasers” for histone lactylation at histone H3 lysine 1 (H3K1) (Moreno-Yruela et al., 2022b). However, the enzymes that produce lactyl-CoA, the enzymes that derive the lactyl group, and other enzymes that participate in the regulation of histone lactylation remain unclear (Hou et al., 2024; Yang et al., 2023a), necessitating further investigation.

FIGURE 1

Studies have demonstrated that inhibition or promotion of glycolysis decreases or increases the total level of Kla, respectively, highlighting the sensitivity of histone lactylation to glycolysis-dependent lactate production (Jin et al., 2022; Irizarry-Caro et al., 2020). As an important component of the TME, lactate links metabolism, epigenetics, and transcription, thereby regulating gene expression. An immunosuppressive microenvironment is established and maintained in part by Kla. By directly binding to lactylation sites on the lysine residues of histones, lactate functions as an epigenetic regulator that directs the transcription of genes involved in damage repair, including arginase-1 (Arg1), and induces the polarization of macrophages toward the M2 phenotype through epigenetic reprogramming (Wang Z. H. et al., 2021). Pyruvate kinase M2 (PKM2) regulates glycolysis by directly interacting with lactate. In addition, lactylation at its K62 site enhances glycolytic activity, resulting in increased expression of Arg1. This regulation suppresses the inflammatory activity of M1 macrophages, promoting polarization toward the M2 phenotype (Wang et al., 2022a).

Histone lactylation exerts crucial epigenetic regulatory effects during tumorigenesis (Yu et al., 2021). Accumulation of lactate in the TME is a common feature of cancer that can induce histone lactylation, thus promoting the development of various types of tumors by disrupting the balance in gene transcription (Certo et al., 2021; Ippolito et al., 2019). Understanding the close relationship between histone lactylation and tumor development may offer novel avenues for developing more effective therapeutic strategies for cancer.

2.2 Non-histone lactylation

Lactylation can occur in non-histone proteins, affecting the structure and function of these proteins. Wan et al. found that peptides with lactylated lysine residues produced distinct immonium ions, which served as a marker for identifying lysine lactylation accurately. They discovered information regarding lactylation substrate proteins and modification sites by searching for these ions in existing human proteomic data resources. These findings suggest that lactylation plays an equally important regulatory role in non-histone proteins. Important cellular functions associated with both healthy and diseased states are mediated by these proteins (Wan et al., 2022). Identifying lactylation sites in non-histone proteins is another focus area of ongoing research in this field (Jing et al., 2024).

Lactylation can also occur in nuclear proteins. Studies have shown that the homologous recombination-associated protein MRE11 is lactylated at its K672 site via a p300-dependent mechanism. This modification leads to DNA end resection, promotes homologous recombination, and induces drug resistance in tumor cells (Chen et al., 2024b). Furthermore, the nuclear protein high-mobility group box-1 (HMGB1) can be lactylated (Yang K. et al., 2022) and subsequently secreted into the cytoplasm through exosomes. In the cytoplasm, lactylated HMGB1 regulates endothelial permeability, inflammation surrounding tumor cells, and stromal remodeling in the TME, thereby influencing the characteristics of the TME (Lan et al., 2020). Moreover, lactylation reduces the binding affinity of HMGB1 for immune cell surface receptors, impairing immune cell recognition and clearance of HMGB1, suppressing anti-tumor immune responses, and promoting cancer progression (Chen et al., 2024b). In a study, proteomic analysis of gastric cancer (GC) cells revealed HMGB1 among the 1,014 proteins with a total of 2,375 lactylation sites. The nucleus contained more than half of these lactylated proteins, whereas the remaining proteins were distributed across other cellular compartments. Lactylation is frequently found in spliceosomes and has been demonstrated to affect RNA splicing (Yang D. et al., 2022). Additionally, nuclear hypoxia-inducible factor 1-alpha (HIF1α) can undergo lactylation. In prostate cancer (PCa), the uptake of excess lactate via MCT1 results in lactylation of HIF1α, stabilizing the protein even under normoxic conditions. This stabilization activates downstream signaling, enhances transcriptional activity, and promotes angiogenesis (Luo et al., 2022). Alanyl-tRNA synthetase 1 (AARS1) has been identified as both a lactate sensor and a lactyltransferase that can lactylate p53 and promote tumorigenesis (Li H. et al., 2024; Ju et al., 2024). In a recent study, pan-cancer multi-omic analysis revealed overexpression of lactylation-related proteins such as glyoxalase 1 (GLO1), HDAC2, HDAC8, and HDAC1 in various tumor tissues (Wu Z. et al., 2024).

With advancements in scientific technology, more lactylation sites will be identified and their roles and regulatory mechanisms will be comprehensively investigated, offering new avenues for therapeutic research. However, studies on non-histone lactylation remain limited, necessitating further investigation into the functions and mechanisms of this modification.

3 Interactions between lactylation and metabolic pathways in tumors

3.1 Glycolysis

In normal cells, energy is derived primarily from OXPHOS or glycolysis. However, aerobic glycolysis or the Warburg effect is considered the predominant mechanism of energy production in tumor cells (Icard et al., 2018). Glycolysis produces high amounts of lactate, and subsequent histone lactylation can regulate gene expression. During glycolysis, glucose undergoes incomplete oxidation, generating two molecules of pyruvate. Pyruvate is reduced to lactate under the action of lactate dehydrogenase. Subsequently, acyltransferases catalyze the conversion of lactate to lactyl-CoA, which modifies lysine residues on histone tails, completing lactylation (Zhang et al., 2019). Therefore, a key element in histone lactylation is the imbalance between glycolysis and the tricarboxylic acid cycle (TAC). Although the glycolytic intermediate lactylglutathione (LGSH) is the source of the lactyl group in histone lactylation, high LGSH levels are associated with an increase in histone lactylation levels of glycolytic enzymes and a notable reduction in glycolysis. Consequently, histone lactylation acts as a feedback loop during glycolysis, with higher blood glucose levels promoting the formation of LGSH and lactylation, which in turn inhibits glycolysis (Gaffney et al., 2020).

Hypoxia is a hallmark of the microenvironment of solid tumors. Under hypoxic conditions, the upregulated expression of serine hydroxymethyltransferase 2 (SHMT2) enhances the glycolytic activity of esophageal cancer (EC) cells. Additionally, glycolysis-derived lactate induces lactylation of SHMT2, stabilizing the protein. Mechanistically, SHMT2 interacts with mitochondrial monofunctional C1-tetrahydrofolate synthase (MTHFD1L), promoting malignant progression in EC (Qiao et al., 2024). A recent study showed that a positive feedback loop involving glycolysis, H3K18 lactylation (H3K18la), and the protein kinases TTK and BUB1B exacerbates dysfunction in pancreatic ductal adenocarcinoma (PDAC) (Li et al., 2024b). These findings indicate that histone lactylation not only occurs during glycolysis but also influences glycolysis, playing a regulatory role in pathological processes (Wang M. et al., 2023). Understanding histone lactylation may provide novel insights into the mechanisms through which the Warburg effect contributes to cancer progression and introduce promising avenues for investigating the interplay between glycolysis and epigenetic modifications in cancer.

3.2 Acetylation

Recent studies have revealed complex crosstalk between histone lactylation and acetylation, both independently and synergistically, providing insights into their roles in tumorigenesis and their potential as therapeutic targets. Both lactylation and acetylation occur on lysine residues. p300, a member of the HAT family, has been identified as the primary “writer” enzyme for lactylation (Dai X. et al., 2022; Chen et al., 2021). Despite their similarities and shared catalytic enzymes, histone lactylation exhibits slower dynamic equilibrium kinetics (24 h) than histone acetylation (6 h), which suggests that acetylation occurs more readily than lactylation under physiological conditions (Dai X. et al., 2022). During lactylation, lactyl-CoA donates lactyl groups to lysine residues (Dai S. K. et al., 2022). Because both lactyl-CoA and acetyl-CoA are derived from pyruvate, the dominance of these pathways can vary across cell types (Gaur et al., 2021). Cells generate lactate under hypoxic conditions; however, the presence of sufficient oxygen promotes the conversion of pyruvate to acetyl-CoA, driving TAC (Zhang et al., 2019). The interaction between acetylation and lactylation has been shown to influence tumor progression. Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is necessary for cancer cells to transition from OXPHOS to aerobic glycolysis. According to a recent study, p300 acetylates the E3-binding protein (E3BP) of PDC at Lys 488, interfering with the interaction of PDHX with dihydrolipoyl transacetylase and preventing the assembly and activation of PDC. The majority of glucose is converted to lactate as a result of this disruption, which promotes aerobic glycolysis and H3K56 lactylation-mediated gene expression, eventually accelerating the growth of malignant tumors (Jiang Z. et al., 2024). A competitive link between histone lactylation and acetylation has also been observed, which indicates that several genes that cannot undergo acetylation are susceptible to lactylation. The ratio of lactylation to acetylation reflects the pathway of pyruvate conversion and may serve as an indicator of a cell’s susceptibility to malignancy (Dai X. et al., 2022). This competitive interplay highlights the importance of understanding the metabolic and epigenetic regulatory processes involved in tumorigenesis.

3.3 Other metabolic pathways

Lipid metabolism and the pentose phosphate pathway (PPP) have been associated with lactylation. Chen et al. conducted a comprehensive lactyl-proteomic and metabolomic analysis on samples from patients with non-small cell lung cancer (NSCLC). The findings revealed that intracellular lactate promotes extracellular lipolysis through lactylation of apolipoprotein C-II (APOC2). Mechanistically, lactate enhances lactylation of APOC2, stabilizing the protein and resulting in the release of free fatty acids, accumulation of Tregs, resistance to immunotherapy, and tumor metastasis (Chen J. et al., 2024). Another study demonstrated that lactate dehydrogenase A (LDHA) is activated under nutrient deprivation by UNC-51-like kinase 1 (ULK1), which phosphorylates serine-196 and promotes lactate production. Subsequently, lactylation of the autophagy-related protein vacuolar protein sorting 34 (Vps34) enhances its binding to phosphoinositide-3-kinase class 3 (PIK3C3) and increases its lipid kinase activity. This process, which facilitates autophagy and lysosomal degradation, is closely associated with cancer progression (Jia et al., 2023). Furthermore, a recent study on cervical cancer found that lactate induces lactylation of discoidin, CUB, and LCCL domain-containing protein 1 (DCBLD1) at the K172 site. This modification stabilizes DCBLD1 expression, leading to an increase in the expression and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), which stimulates the PPP and promotes the progression of cervical cancer (Meng et al., 2024). Additionally, lactylation of NMNAT1 can support the survival of pancreatic cancer cells by maintaining the nuclear NAD + salvage pathway (Huang H. et al., 2024).

These findings highlight the intricate crosstalk between lactylation and other metabolic pathways. However, research in this area remains limited. Understanding this crosstalk and the underlying mechanisms may provide novel avenues for preventing tumor progression, developing targeted therapeutic approaches, and optimizing existing treatment strategies.

4 Role of lactylation in tumor progression

4.1 Role in tumor initiation and growth

Studies have shown a strong correlation between lactylation and tumor initiation. In colorectal cancer (CRC), the overall level of Kla is negatively correlated with the prognosis. Among the lactylated proteins identified in CRC, the lysine acetyltransferase KAT8 mediates the lactylation of elongation factor 1 alpha (eEF1A2) at the K408 site, enhancing elongation during translation and protein synthesis, thus promoting tumorigenesis (Xie et al., 2024). In a study on cutaneous melanoma (CM), Yu et al. found that histone lactylation facilitated tumorigenesis by promoting the expression of YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) (Yu et al., 2021). Similarly, in CRC, histone lactylation increases the stability of potassium channel subfamily K member 6 (Kcnk6) in a YTHDF2-dependent manner, enhancing the activity of potassium channels, inducing the activation of the NOD-like receptor thermal protein domain-associated protein 3 (Nlrp3) inflammasome, and eventually driving inflammation-induced carcinogenesis (Yuan et al., 2024).

Furthermore, lactylation is involved in tumor cell proliferation (Fu et al., 2024; Zang et al., 2024). Miao et al. demonstrated that hypoxia promoted lactylation of β-catenin, enhancing its stability and driving CRC cell proliferation via the Wnt signaling pathway (Miao et al., 2023). Insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) play crucial roles in regulating glycolysis in tumors. In lung cancer, IGF1R is highly expressed and its lactylation is associated with the malignant proliferation of tumor cells. Lactate enhances the stability of IGF1R protein, forming a feedback loop that promotes glycolysis and lactate production (Zhang R. et al., 2024). The histone H3 variant CENPA interacts with yin and yang 1 (YY1) to promote the production of neuropilin 2 (NRP2) and cyclin D1 (CCND1). Lactylation of CENPA at K124 promotes its activation, increasing the expression of its target genes and accelerating tumor development in hepatocellular carcinoma (HCC) (Liao et al., 2023). The transcription of serine/arginine-rich splicing factor 10 (SRSF10) is enhanced by increased aerobic glycolysis, which also increases histone lactylation levels at the c-Myc promoter. This phenomenon promotes alternative splicing of BCL2-like 1 (Bcl-x) and murine double minute 4 (MDM4), facilitating the proliferation of HCC cells (Pandkar et al., 2023; Yao and Yang, 2024). In anaplastic thyroid cancer (ATC), aerobic glycolysis increases cellular lactate utilization and overall protein lactylation. Specifically, H4K12la activates genes essential for the proliferation of ATC cells. The oncogenic mutation BRAFV600E further promotes glycolysis, re-inducing lactylation and leading to H4K12la-driven dysregulation of transcription and the cell cycle (Wang X. et al., 2023). Li et al. performed immunohistochemical analysis on 60 triple-negative breast cancer samples and found increased levels of total lactylated proteins and specific histone H4K12 lactylation in the samples. H4K12la may bind to the schlafen 5 (SLFN5) promoter region, suppressing the expression of SLFN5 and leading to altered gene profiles and reduced apoptosis (Li J. et al., 2024).

Tumor cells exhibit remarkable plasticity (Chiodi and Mondello, 2020). The acquisition of stem cell-like properties is a major factor contributing to the self-renewal and long-term proliferation of cancer cells (Li Q. et al., 2024; Han et al., 2020). Lactate serves as a crucial metabolite, signaling molecule, and energy source during the development of HCC. Intracellular lactylation is considered a contributing factor in the development of HCC. Compared with HCC cells, liver cancer stem cells (LCSCs), the source of phenotypic and functional heterogeneity in HCC, exhibit enhanced glycolysis, lactate accumulation, and lactylation. H3K56la is closely associated with tumor initiation and the stemness of LCSCs. In a study, a comprehensive analysis of the lactylome and proteome of LCSCs showed that lactylation of aldolase A (ALDOA) at K230/322 enhanced the function of DDX17 in maintaining stemness. However, the impact of Kla on HCC stem cells remains unclear. Targeting lactylated ALDOA represents a promising therapeutic strategy for HCC (Feng et al., 2024). In glioblastoma (GBM), lactylation of histone H3 increases the expression of LINC01127, which directs polymerase II (POLR2A) to the mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) promoter region. This interaction activates the JNK pathway, regulating the self-renewal of GBM cells (Li et al., 2023).

4.2 Role in tumor invasion and migration

Invasion and migration are hallmarks of malignant tumors and significantly impact treatment outcomes and prognosis. Approximately 80% of cases of renal cell carcinoma (RCC), one of the three main cancers of the urinary system, are attributed to clear cell renal cell carcinoma (ccRCC). According to a bioinformatic study, FK506-binding protein 10 (FKBP10) is essential for the glycolytic pathway that leads to metastasis in ccRCC. FKBP10 directly interacts with LDHA via its C-terminal region, enhancing the phosphorylation of LDHA-Y10. This process leads to an overactive Warburg effect and histone lactylation (Liu R. et al., 2024). Lactylation at H3K18 is associated with several malignant features in tumors (Hou et al., 2024). Zhou et al. found that G protein-coupled receptor 37 (GPR37) was significantly overexpressed in human CRC specimens and was correlated with a poor prognosis. Mechanistically, GPR37 promotes LDHA expression and glycolysis by activating the Hippo pathway, which increases H3K18la levels, upregulates chemokine CXC motif ligand 1 (CXCL1) and CXCL5, and enhances tumor cell migration (Zhou et al., 2023). In GC, dynamic H3K18 lactylation activates the transcription of vascular cell adhesion molecule 1 (VCAM1), which stimulates downstream AKT–mTOR signaling, thereby promoting the proliferation and migration of GC cells. Therefore, H3K18 lactylation may serve as a therapeutic target for GC (Zhao Y. et al., 2024). In HCC, proline-5-carboxylate reductase 1 (PYCR1) modulates the transcription of insulin receptor substrate 1 (IRS1) by influencing H3K18 lactylation in its promoter region, thus driving metastasis and promoting other malignant characteristics of HCC cells (Wang H. et al., 2024).

Epithelial–mesenchymal transition (EMT) is a crucial mechanism through which tumor cells acquire metastatic potential. EMT decreases cell-to-cell interactions and promotes migration and motility (Dongre and Weinberg, 2019). This process is hijacked in cancer to enable morphological and motility-related changes that stimulate invasion and migration (Lu et al., 2019). Glucose transporter 3 (GLUT3) plays an important role in glycolysis in cancer. In a study on GC, single-cell sequencing revealed significant upregulation of GLUT3 expression in primary and metastatic tumor tissues. This increased expression of GLUT3 was positively correlated with the expression of LDHA and the activity of lactylation-associated pathways and was functionally associated with EMT (Yang et al., 2023a). Lysyl oxidase (LOX) secreted by CAFs controls EMT through TGFβ/IGF1 signaling and enhances PD-L1 expression through histone lactylation (Li Z. et al., 2024). In pancreatic cancer, Rho GTPase Rif (RHOF) promotes the lactylation and nuclear translocation of Snail 1 by enhancing PKM2-mediated glycolysis, thereby inducing EMT (Zhao R. et al., 2024). In HCC, increased lactylation at H3K9 and H3K56 activates the transcription of endothelial-specific molecule 1 (ESM1) to promote EMT (Zhao P. et al., 2024).

Angiogenesis is crucial for tumor cells to acquire nutrients and metastasize (Zheng et al., 2023; Bhat et al., 2021). Studies have shown that the lactation of H3K9 in Endothelial cells can regulate Vascular Endothelial Growth Factor (VEGF), thereby inducing angiogenesis (Fan et al., 2024). PCa is one of the most prevalent cancers in adult men worldwide. Recent studies have shown that the expression of the hyaluronan-binding protein KIAA1199 is correlated with tumor stage, HIF-1α overexpression, and angiogenic markers in PCa. Overexpression of KIAA1199 enhances the production of secretory vascular endothelial growth factor A (VEGFA), promoting angiogenesis and vasculogenic mimicry (VM). In a study, ChIP-PCR and dual-luciferase reporter assay showed that HIF-1α enhances the transcription of KIAA1199. Mechanistically, lactate imported via MCT1 stabilizes HIF-1α through lactylation, enhancing the transcription of KIAA1199 (Luo et al., 2022). HCC is characterized by abundant vasculature. Upon its activation by histone lactylation and c-Myc, Golgi phosphoprotein 73 (GP73) leads to the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which in turn enhances the pro-angiogenic function of GP73 (Ye et al., 2024).

These findings emphasize the crucial roles of lactylation in tumor invasion, migration, and angiogenesis, providing potential therapeutic targets for metastatic and vascularized tumors.

4.3 Role in immune regulation

Tumors form a complex ecosystem, with various immune cells being intricately involved. Studies have highlighted the important role of lactylation in immune regulation in tumors.

During tumor progression, cancer cells adopt diverse mechanisms to evade immune surveillance, such as downregulating antigen presentation pathways or inducing inhibitory immune checkpoints (Jhunjhunwal et al., 2021). Lactate-driven histone lactylation in KRAS-mutant tumor cells has been shown to activate the transcription of circATXN7, a circular RNA that interacts with NF-κB. circATXN7 sequesters p65 in the cytoplasm by binding to and masking the nuclear localization signal motif of the NF-κB p65 subunit, increasing the susceptibility of tumor-specific T cells to activation-induced cell death (AICD) and promoting immune evasion (Zhou et al., 2024). In NSCLC, H3K18la enhances immune evasion by activating the pore membrane protein 121 (POM121)/MYC/PD-L1 axis (Zhang C. et al., 2024). In GC, high lactylation levels are strongly correlated with poor overall survival and disease progression. Mechanistic experiments have shown that high lactylation levels are characterized by extensive macrophage infiltration, increased genomic instability, and a high risk of immune dysfunction in tumors (Yang et al., 2023b). In experimental models of PCa with PTEN/p53 abnormalities, activation of the Wnt/β-catenin pathway has been shown to result in lactylation at H3K18 in tumor cells and tumor-associated macrophages (TAMs), contributing to immune evasion (Chaudagar et al., 2023).

Cancer cells exploit immune cells, such as macrophages, CD8⁺ T cells and Tregs, to shape an immunosuppressive TME (Lei et al., 2020). Tumor-derived lactate is a critical driver of TAM polarization (Fang et al., 2023). For instance, Li et al. found that tumor-derived lactate promoted H3K18la, suppressing the transcription of RARγ in macrophages. This process enhanced IL-6 levels in the TME, activating STAT3 signaling in CRC cells and promoting the polarization of macrophages toward the M2 phenotype (Li X. M. et al., 2024). In neuroblastoma (NB), hexokinase-3 (HK3), a key enzyme in glucose metabolism, is correlated with M2 macrophage infiltration, increased lactate secretion by tumor cells, and histone lactylation (Wu X. et al., 2024). Proprotein convertase subtilisin/kexin type 9 (PCSK9) can inhibit M1 polarization by increasing lactate levels, promoting protein lactylation, and strengthening the activity of macrophage migration inhibitory factor (MIF) (Wang L. et al., 2022). In cervical cancer, lactate secreted by tumor cells increases H3K18la levels and promotes M2 polarization by upregulating glycerol-3-phosphate dehydrogenase 2 (GPD2), thereby supporting tumor progression (Huang C. et al., 2024). In advanced stages, monocyte-derived macrophages (MDMs) increase in number and lactate-driven histone lactylation increases IL-10 expression, forming an immunosuppressive TME by suppressing T-cell activity (De Leo et al., 2024).

Lactylation can influence the activity of T cells, one of the key components of the TME. Activation and functional differentiation of CD8⁺ T cells are regulated by lactate-associated metabolic pathways. Histone modifications such as H3K18la and H3K9la are enriched in CD8⁺ T cells, serving as transcriptional initiation factors for key regulatory genes (Raychaudhuri et al., 2024). SRSF10, which is upregulated in various tumors, enhances glycolysis-related enzymes, such as LDHA, increasing intracellular and extracellular lactate levels. This increase induces histone lactylation and amplifies SRSF10 expression. In addition, tumor-derived lactate can induce H3K18la in macrophages, activating transcription and enhancing cellular activity. M2 macrophages, in turn, inhibit CD8⁺ T cell infiltration, exacerbating the immunosuppressive TME (Cai et al., 2024).

Additionally, regulatory T cells (Tregs) are crucial for the development and maintenance of the suppressive TME (Li et al., 2020). A study showed that lactylation of lysine residues in membrane-organizing extension spike protein (MOESIN) increased the expression of forkhead box P3 (FOXP3) and enhanced the regulation of transforming growth factor-beta (TGF-β) signaling, thus sustaining Treg-mediated immunosuppression and promoting TME formation (Gu et al., 2022a). Lactylation at K72 in membrane proteins regulates Treg cell generation by enhancing their interactions with TGF-β receptors (Gu et al., 2022b). STAT5 expression promotes glycolysis in acute myeloid leukemia (AML) cells, leading to lactate accumulation. Excess lactate triggers the nuclear translocation and histone lactylation of E3BP, eventually inducing the transcription of PD-L1. Therefore, patients with AML characterized by STAT5-driven glycolysis and lactate accumulation may benefit from PD-1/PD-L1 blockade therapies (Huang et al., 2023) (Figure 2).

FIGURE 2

Tumor immune regulation is a critical aspect of understanding tumorigenesis, with profound implications for developing novel treatments, elucidating mechanisms underlying drug resistance, and improving patient prognosis. Lactylation has demonstrated substantial research potential in this domain. Ongoing studies will likely uncover novel therapeutic targets, advancing the development of novel immunotherapies.

4.4 Role in the genome

As a PTM, lactylation inevitably exerts significant effects on the genome. TIMs, crucial players in tumor immune evasion, are regulated by various epigenetic mechanisms. Lactylation-induced activation of the m6A–YTHDF1 axis mediated by methyltransferase-like 3 (METTL3) improves the translation efficiency of JAK1 and phosphorylation of STAT3, supporting the immunosuppressive properties of TIMs (Xiong et al., 2022). N1-methyladenosine (m1A) RNA modification serves as a key regulator of RNA metabolism. Histone lactylation can upregulate AlkB homolog 3 (ALKBH3), which in turn suppresses m1A modification of speckled protein 100A (SP100A), weakening the formation of tumor-suppressive promyelocytic leukemia (PML) protein condensates and facilitating the malignant transformation of tumor cells (Gu X. et al., 2024). Therapeutic resistance and tumor development are significantly influenced by cellular plasticity. In a study, multi-omic analysis showed that the expression of zinc finger E-box-binding homeobox 1 (ZEB1) is indicative of an intermediate state that tumor cells go through during the progression of neuroendocrine prostate cancer (NEPC). EMT, stemness, and neuroendocrine traits are present in this stage. ZEB1 directs tumor cells toward glycolysis for energy production by controlling the transcription of numerous important glycolytic enzymes. Histone lactylation induced by lactate accumulation during this process improves cellular plasticity and chromatin accessibility (Wang D. et al., 2024).

These findings highlight the essential role of lactylation in modulating genomic and epigenomic landscapes, influencing tumor cell behavior, and promoting malignancy. Understanding these mechanisms may offer promising avenues for targeted therapeutic interventions in cancer.

4.5 Role in treatment resistance

Despite significant advancements in the treatment of cancer, therapeutic resistance associated with molecular and clinical relapse remains prevalent, resulting in a poor prognosis. Therefore, understanding the mechanisms underlying therapeutic resistance is necessary to improve the treatment of cancer. Recent studies have shown that lactylation may contribute to treatment resistance in cancer (Takata et al., 2024).

Resistance to traditional anti-cancer treatments has been closely associated with lactylation in various tumor types. Lactylation of Nijmegen breakage syndrome protein 1 (NBS1) at lysine 388 (K388) is essential for the formation of the MRE11–RAD50–NBS1 (MRN) complex and the accumulation of DNA repair proteins at DNA double-strand break sites. However, this process is associated with adverse outcomes of neoadjuvant chemotherapy (Yang et al., 2023b). In metastatic CRC, bevacizumab is an important drug in first- and second-line treatments. Studies have shown that patients with bevacizumab-resistant CRC exhibit increased levels of histone lactylation, which promotes the transcription of recombinant rubicon-like autophagy enhancer (RUBCNL) through interactions with beclin 1 (BECN1). This process drives the maturation of autophagosomes, recruitment of the class III phosphoinositide 3-kinase complex, and proliferation and survival of cancer cells under hypoxic conditions (Li W. et al., 2024). Patients with bladder cancer (BCa) often develop resistance to cisplatin. H3K18la drives the transcription of Y-box-binding protein 1 (YBX1) and YY1, which are closely associated with cisplatin resistance (Li et al., 2024h). Similarly, histone lactylation plays a role in the development of cisplatin resistance in oral squamous cell carcinoma (OSCC) (Huang G. et al., 2024). In a study on GBM, interactions between aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) and PKM2 were found to enhance PKM2 tetramerization in glioblastoma stem cells (GSCs), promoting lactate accumulation. Proteomic analysis of these GSCs revealed lactylation of X-ray repair cross-complementing protein 1 (XRCC1) at K247. Lactylated XRCC1 enhanced DNA repair, conferring drug resistance in ALDH1A3-overexpressing GBM cells (Li et al., 2024). Temozolomide (TMZ) resistance is a major barrier to the successful treatment of GBM. Studies have shown that H3K9la significantly enriches the LUC7L2 promoter, activating its transcription and promoting TMZ resistance in GBM (Yue et al., 2024). Other studies on the role of lactylation in the acquisition of resistance to standard anti-cancer therapies are highlighted in Table 1 (Lu Y. et al., 2024; Chu et al., 2023; Duan et al., 2023; Sun X. et al., 2023).

Immune checkpoint blockade (ICB) therapies have shown remarkable efficacy across multiple tumor types. However, resistance to these therapies is increasingly being reported. The expression of solute carrier family two member 1 (SLC2A1), which encodes the GLUT1 protein, is different between lung squamous cell carcinoma (LUSC) tissues and normal lung tissues. In a study, GLUT1 was identified as an independent prognostic factor for LUSC. According to LASSO analysis, high protein lactylation levels were associated with high SLC2A1 expression. Furthermore, SLC2A1 expression was found to have a negative correlation with the expression of TIGIT, CTLA4, LAG3, PD-1, and other common immune checkpoints (Hao et al., 2024). Increased levels of histone lactylation have been associated with a poor response to immunotherapy in head and neck squamous cell cancer (HNSCC). H3K9la can control downstream interleukin-11 (IL-11), which activates the transcription of various immune checkpoint genes in CD8⁺ T cells through the JAK2/STAT3 pathway. In addition, H3K9la is strongly correlated with IL-11 expression and a poor response to immunotherapy in patients with HNSCC in clinical settings (Wang R. et al., 2024). APOC2 can also promote resistance to immunotherapy in NSCLC (Chen J. et al., 2024).

Understanding the mechanisms through which lactylation contributes to drug resistance is essential for improving treatment outcomes in patients with cancer.

4.6 Microorganisms participate in lactation modification

The microbiome may play an important role in tumor initiation, progression, and metastasis. Microorganisms can influence cancer-related processes by modulating immune responses, promoting inflammation, and producing carcinogenic substances. Numerous intratumoral bacteria, such as E. coli, have been found to reside within tumors and contribute to liver metastasis of colorectal cancer (CRLM). E. coli inhibits the recruitment of NF-κB to the Nlrp3 promoter in macrophages by inducing lactylation of retinoic acid-inducible gene 1 (RIG-I), which suppresses the transcription of Nlrp3 and mediates M2 polarization. The absence of Nlrp3 impacts the immunosuppressive activity of Tregs and the anti-tumor responses of CD8⁺ T cells (Gu J. et al., 2024). In a prospective study, Yang et al. investigated the lactylome of patients with HCC with hepatitis B virus (HBV) infection through integrated genomic and proteomic analysis of the tumor and surrounding liver tissues. The results revealed 9,275 lactylation sites; of which, 9,256 sites were found on non-histone proteins, indicating that Kla is a ubiquitous alteration that affects both histone and non-histone proteins and performs other functions in addition to transcriptional regulation. Furthermore, analysis of the lactylome revealed lactylation-dependent metabolic adaption pathways in HBV-related HCC (Y et al., 2023). Gut microorganisms can play a role in disease development by interacting with the host genome through epigenetic factors, such as long non-coding RNAs (lncRNAs). Wang et al. measured transcriptomic alterations in a human colon cell line infected with the common gut pathogen Salmonella typhimurium SL1344. The results showed that bacterial lipopolysaccharides (LPSs) led to increased production of LINC00152, which was controlled by histone lactylation. The expression of LINC00152 was higher in CRC tissues than in adjacent normal tissues (Wang et al., 2022c).

4.7 Other mechanisms

In addition to its well-known tumor-suppressive function in lung cancer, liver kinase B1 (LKB1) is reported to be involved in cellular senescence. In LKB1-deficient A549 cells, overexpression of LKB1 increases H4K8 and H4K16 levels and causes lactate generation. By controlling the production of telomerase reverse transcriptase (TERT), this inhibition reduces telomerase activity and causes telomere dysfunction, providing novel insights into the function of LKB1-mediated cellular senescence in lung cancer (Liu M. et al., 2024).

Autophagy is a lysosome-mediated self-degradation process that recycles damaged organelles and long-lived proteins, maintaining cellular homeostasis under metabolic stresses, such as starvation and hypoxia. Lactate has been shown to regulate autophagy. Transcription factor EB (TFEB), a key regulator of lysosomal biogenesis and autophagy, undergoes covalent lactylation, leading to its stabilization and increased activity, which enhances autophagic flux (Huang Y. et al., 2024). Furthermore, histone lactylation promotes autophagosome maturation, which is essential for the proliferation and survival of hypoxic cancer cells (Li W. et al., 2024). Lactylation of PIK3C3/VPS34 at K356 and K781 through lysine acetyltransferase 5 (KAT5) can enhance the association of VPS34 with BECN1, ATG14, and UVRAG, promoting autophagy and other lysosomal degradation pathways (Sun W. et al., 2023) (Figure 3).

FIGURE 3

5 Predicting clinical prognosis using lactylation-related genes

With the emergence of new bioinformatic technologies, such as machine learning, and publicly available databases, clinicians can analyze gene expression profiles to predict patient prognosis in cancer (Yin et al., 2024; Zheng et al., 2024; Pan et al., 2024; Cai et al., 2023). Studies have shown that lactylation is closely associated with the clinical outcomes of patients with cancer (Chen et al., 2024d; Lu X. et al., 2024; Liu J. et al., 2024). Feng et al. used machine learning algorithms to construct a risk model for CM based on lactylation-related genes using data from the TCGA and GEO databases. Eight genes, namely, TMSB4X, CRABP2, WAS, LAP3, SATB1, GATAD2A, CALML5, and MDC1 were identified as candidate lactylation-related genes for constructing the model. Patients in the TCGA-CM cohort were divided into high- and low-risk groups based on the median risk score. In the high-risk group, the expression levels of CRABP2, GATAD2A, and MDC1 were substantially high, whereas those of LAP3, SATB1, and WAS were low. In both TCGA and GEO cohorts, survival analysis revealed a negative correlation between the risk scores and overall survival (OS) in patients with CM (Feng et al., 2023). In another study, machine learning revealed SMAD4, KRAS, TTN, CDKN2A, and TP53 as the top five mutated genes in PDAC. In addition, the researchers investigated mutation trends in different PDAC subgroups based on lactylation scores. The tumor mutation burden (TMB) was positively correlated with lactylation scores, with high-scoring clusters having a greater TMB than low-scoring clusters. Compared with patients with low TMB and lactylation scores, those with high TMB and lactylation scores had notably shorter OS (Peng et al., 2024). In a study on cervical cancer, lactylation-related genes (KRGs) were used to classify tumors into two subtypes, C1 and C2. The C2 cluster exhibited suppressed glycolysis and enhanced OXPHOS, which corresponded to higher survival rates. Additionally, a prognostic model based on two lactate signaling genes, ISY1 and PPP1R14B, was developed. A negative correlation was observed between PPP1R14B expression and CD8⁺ T cell infiltration, which was associated with low survival rates. The prognostic model was validated in two independent cohorts of patients with cervical cancer, one treated in Uganda (n = 106) and the other in Seoul (n = 300). Survival analysis revealed considerably lower OS or disease-free survival (DFS) rates among high-risk patients (He et al., 2024). Chao et al. investigated the relationship between lactylation and OS or progression-free survival (PFS) in ovarian cancer. Higher H3K18la levels were associated with worse PFS (p < 0.001) and OS (p = 0.028). Multivariate Cox regression analysis showed that H3K18la was an independent risk factor for PFS (p = 0.001). Moreover, H3K18la levels were correlated with the tumor stage (p = 0.037). Altogether, high H3K18la levels were associated with a poor prognosis in epithelial ovarian cancer (Chao et al., 2024).

Understanding the role of lactylation in cancer prognosis can assist clinicians in devising personalized treatment plans, evaluating therapeutic efficacy, and monitoring adverse reactions (Hao et al., 2024; Yu et al., 2024). As mentioned earlier, lactylation is found in various tumor types; however, studies investigating its clinical prognostic value remain limited. Future research in this area is essential to broaden the understanding and application of lactylation-related biomarkers in cancer.

6 Therapeutic strategies targeting lactylation

Lactylation plays an important role in the development and progression of various tumors, making it a promising therapeutic target for cancer (Li X. M. et al., 2024; Sun L. et al., 2023). With the deepening of research on lactylation in recent years, numerous targeted therapies have been developed for cancer, primarily encompassing the following three categories: inhibitors of lactate metabolism, lactate transporter proteins, and lactylation sites (Figure 1).

LDHA inhibitors, dexmedetomidine (Dex), and fargesin (FGS) are inhibitors of lactate metabolism. In patients with HCC, the combination of anti-PD-1 therapy and LDHA inhibitors has demonstrated stronger anti-tumor effects than monotherapy with anti-PD-1 antibodies (Gu et al., 2022b). In GBM, the LDHA inhibitor oxamate can enhance the efficacy of CAR-T cell therapy by inhibiting the lactylation of exonucleases and C-C motif chemokine receptor 8 (CCR8) (Sun T. et al., 2023). In addition, Dex can suppress glycolysis and reduce lactylated c-Myc levels, thereby decreasing the stability of c-Myc protein and inhibiting the migratory and invasive abilities and glycolytic activity of GBM cells (Zhu and Zhang, 2024). In NSCLC, FGS interacts with PKM2 to regulate glycolysis and pyruvate metabolism, suppressing lactate production and LDHA expression. Moreover, it inhibits tumor-associated histone lactylation, thereby exerting anti-tumor effects (Guo et al., 2024).

As mentioned earlier, lactate is transported between cells via MCTs. MCT4, located on glycolytic tumor cells, transports the lactate produced by these cells to the intercellular space. This lactate is subsequently internalized by oxidative tumor cells via MCT1. BAY-8002 and AZD3965 are two potent inhibitors of MCT1 that can alter its open conformation and inhibit lactate transport in the TME (Wang N. et al., 2021).

Inhibitors of lactylation sites directly target lactylation to achieve anti-cancer effects. Accumulation of lactate in CRC cells activates the transcription of the m5C methyltransferase NSUN2 via H3K18la. Lactylation of NSUN2 at K356 contributes to its oncogenic role. Therefore, combining NSUN2 inhibitors with immunotherapy represents a promising therapeutic strategy for CRC (Chen B. et al., 2024). Cancer stem cells can reduce the effectiveness of anti-cancer medications by driving tumor development, progression, and recurrence. A triterpenoid anti-cancer substance called dihydrocelastrol (DML) prevents carcinogenesis in liver cancer by interfering with histone lactylation induced by metabolic stress (Pan et al., 2022). Royal jelly acid, a component of traditional Chinese medicine, exerts inhibitory effects on lactylation. For instance, it suppresses H3K9la and H3K14la to reduce tumorigenicity in HCC (Xu et al., 2023).

Effective therapeutic strategies targeting lactylation are lacking at present. Therefore, developing broad-spectrum inhibitors of lactylation is necessary. Lactylation plays an oncogenic role in various tumor types, thus serving as a promising therapeutic target for cancer. Further studies are warranted to explore and optimize lactylation-targeted strategies for the treatment of cancer in clinical settings.

7 Discussion

While lactylation research is still in its early stages, emerging evidence highlights lactylation’s potential as both a diagnostic/prognostic biomarker and a therapeutic target across diverse cancer types. With continued investigation into its regulatory enzymes, context-specific roles, and clinical translation, lactylation-based strategies may pave the way for more precise, metabolism-driven cancer therapies that can enhance patient outcomes and overcome resistance mechanisms.

Despite the growing interest in targeting lactylation as a cancer therapeutic strategy, several critical knowledge gaps and shortcomings hinder its clinical translation. First, the enzymatic machinery that governs histone lactylation remains incompletely characterized. Although p300 and HBO1 have been identified as potential lactyltransferases, the full complement of “writers,” “erasers,” and “readers” of lactylation is largely unknown, including the enzymes responsible for generating and regulating lactyl-CoA. This limited understanding impairs our ability to design specific modulators of lactylation. Second, most of the compounds described—such as LDHA inhibitors, oxamate, and dexmedetomidine—impact broad metabolic or epigenetic pathways rather than selectively targeting lactylation, raising concerns about off-target effects and therapeutic specificity.

Another significant gap lies in the tumor-type specificity and context dependency of lactylation. While lactylation appears to promote tumor progression in various cancers, it is not yet clear why certain tumor types rely more heavily on lactylation or how tumor microenvironmental differences shape lactylation dynamics. This lack of precision complicates the development of broadly effective therapies. Moreover, there is a noticeable absence of clinically validated biomarkers or non-invasive tools to measure lactylation activity in patients, making it difficult to stratify patients or monitor therapeutic responses.

Importantly, although some studies suggest lactylation plays a role in modulating the immune microenvironment—such as through macrophage polarization and Treg activation—detailed mechanistic insights into how lactylation-targeted therapies influence immune cell function are missing. Lastly, while initial combinations with immunotherapies have shown promise, systematic evaluations of combination strategies and potential resistance mechanisms to lactylation-targeted agents are lacking. Addressing these gaps through mechanistic, translational, and clinical research will be essential for realizing the full therapeutic potential of lactylation in cancer.

8 Conclusion

Lactylation, a PTM first identified in 2019, has received increased attention from researchers over the past 5 years for its important role in cancer. It not only participates in tumor pathogenesis but also serves as a potential prognostic biomarker and therapeutic target. Studies have demonstrated that lactylation impacts key malignant features, such as tumor initiation, growth, metastasis, immune regulation, and therapeutic resistance. Furthermore, genes associated with lactylation are closely related to clinical outcomes, highlighting the potential of lactylation as a therapeutic target. However, using lactylation as a diagnostic biomarker or therapeutic target is associated with several challenges. As discussed earlier, lactylation sites associated biological processes, and the regulatory molecules or pathways involved in lactylation vary across tumor types, complicating the development of lactylation as a universal therapeutic target for cancer. Moreover, due to the lack of universal and efficient detection methods, research on the prediction of patient clinical prognosis related to lactylation-modified genes is still insufficient in many tumor types.In addition, effective and selective lactylation inhibitors are still lacking. During the development of new inhibitors, the possibility of off-target effects, the challenges of tissue-specific drug delivery, and the need for reliable biomarkers to monitor treatment responses should also be taken into account. Despite these challenges, lactylation holds promise as a highly effective diagnostic/prognostic biomarker and therapeutic target for cancer owing to its unique role in disease progression.

Existing studies have introduced valuable avenues for investigating the pathophysiological, diagnostic, prognostic, and therapeutic roles of lactylation in tumors. Future research directions may focus on high-throughput screening to identify lactylation regulators, in vivo studies to test therapeutic effects, development of tissue-specific delivery systems, or the use of advanced techniques such as ChIP-seq or single-cell RNA-seq to describe lactylation dynamics in the tumor microenvironment. Further in-depth and innovative research will improve the understanding of the role of lactylation in tumor progression, laying a robust theoretical foundation for the clinical application of lactylation-targeted strategies. This progress may significantly benefit patients that alleviating the disease burdens caused by malignant tumors.

References

• 1

  Apostolova P. Pearce E. L. (2022). Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment. Trends Immunol.43 (12), 969–977. 10.1016/j.it.2022.10.005

  • CrossRef
  • Google Scholar

• 2

  Bhat S. M. Badiger V. A. Vasishta S. Chakraborty J. Prasad S. Ghosh S. et al (2021). 3D tumor angiogenesis models: recent advances and challenges. J. Cancer Res. Clin. Oncol.147 (12), 3477–3494. 10.1007/s00432-021-03814-0

  • CrossRef
  • Google Scholar

• 3

  Brooks G. A. (2018). The science and translation of lactate Shuttle theory. Cell Metab.27 (4), 757–785. 10.1016/j.cmet.2018.03.008

  • CrossRef
  • Google Scholar

• 4

  Brooks G. A. (2020). Lactate as a fulcrum of metabolism. Redox Biol.35, 101454. 10.1016/j.redox.2020.101454

  • CrossRef
  • Google Scholar

• 5

  Cai D. Yuan X. Cai D. Q. Li A. Yang S. Yang W. et al (2023). Integrative analysis of lactylation-related genes and establishment of a novel prognostic signature for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol.149 (13), 11517–11530. 10.1007/s00432-023-04947-0

  • CrossRef
  • Google Scholar

• 6

  Cai J. Song L. Zhang F. Wu S. Zhu G. Zhang P. et al (2024). Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma. Cancer Commun. (Lond)44, 1231–1260. 10.1002/cac2.12607

  • CrossRef
  • Google Scholar

• 7

  Carneiro L. Asrih M. Repond C. Sempoux C. Stehle J. C. Leloup C. et al (2017). AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice. Mol. Metab.6 (12), 1625–1633. 10.1016/j.molmet.2017.10.005

  • CrossRef
  • Google Scholar

• 8

  Certo M. Tsai C. H. Pucino V. Ho P. C. Mauro C. (2021). Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat. Rev. Immunol.21 (3), 151–161. 10.1038/s41577-020-0406-2

  • CrossRef
  • Google Scholar

• 9

  Chao J. Chen G. d. Huang S. T. Gu H. Liu Y. Y. Luo Y. et al (2024). High histone H3K18 lactylation level is correlated with poor prognosis in epithelial ovarian cancer. Neoplasma71 (4), 319–332. 10.4149/neo_2024_240127N41

  • CrossRef
  • Google Scholar

• 10

  Chaudagar K. Hieromnimon H. M. Kelley A. Labadie B. Shafran J. Rameshbabu S. et al (2023). Suppression of tumor cell lactate-generating signaling pathways Eradicates murine PTEN/p53-deficient Aggressive-variant prostate cancer via macrophage Phagocytosis. Clin. Cancer Res.29 (23), 4930–4940. 10.1158/1078-0432.CCR-23-1441

  • CrossRef
  • Google Scholar

• 11

  Chen A. N. Luo Y. Yang Y. H. Fu J. T. Geng X. M. Shi J. P. et al (2021). Lactylation, a novel metabolic reprogramming Code: Current Status and prospects. Front. Immunol.12, 688910. 10.3389/fimmu.2021.688910

  • CrossRef
  • Google Scholar

• 12

  Chen B. Deng Y. Hong Y. Fan L. Zhai X. Hu H. et al (2024e). Metabolic Recoding of NSUN2-mediated m(5)C modification promotes the progression of colorectal cancer via the NSUN2/YBX1/m(5)C-ENO1 positive feedback loop. Adv. Sci. (Weinh)11 (28), e2309840. 10.1002/advs.202309840

  • CrossRef
  • Google Scholar

• 13

  Chen H. Li Y. Li H. Chen X. Fu H. Mao D. et al (2024a). NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature631 (8021), 663–669. 10.1038/s41586-024-07620-9

  • CrossRef
  • Google Scholar

• 14

  Chen J. Zhao D. Wang Y. Liu M. Zhang Y. Feng T. et al (2024c). Lactylated apolipoprotein C-II induces immunotherapy resistance by promoting extracellular lipolysis. Adv. Sci. (Weinh)11 (38), e2406333. 10.1002/advs.202406333

  • CrossRef
  • Google Scholar

• 15

  Chen Y. Chang L. Hu L. Yan C. Dai L. Shelat V. G. et al (2024d). Identification of a lactylation-related gene signature to characterize subtypes of hepatocellular carcinoma using bulk sequencing data. J. Gastrointest. Oncol.15 (4), 1636–1646. 10.21037/jgo-24-405

  • CrossRef
  • Google Scholar

• 16

  Chen Y. Wu J. Zhai L. Zhang T. Yin H. Gao H. et al (2024b). Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell187 (2), 294–311 e21. 10.1016/j.cell.2023.11.022

  • CrossRef
  • Google Scholar

• 17

  Chiodi I. Mondello C. (2020). Life style factors, tumor cell plasticity and cancer stem cells. Mutat. Res. Rev. Mutat. Res.784, 108308. 10.1016/j.mrrev.2020.108308

  • CrossRef
  • Google Scholar

• 18

  Chu Y. D. Cheng L. C. Lim S. N. Lai M. W. Yeh C. T. Lin W. R. (2023). Aldolase B-driven lactagenesis and CEACAM6 activation promote cell renewal and chemoresistance in colorectal cancer through the Warburg effect. Cell Death Dis.14 (10), 660. 10.1038/s41419-023-06187-z

  • CrossRef
  • Google Scholar

• 19

  Dai S. K. Liu P. P. Li X. Jiao L. F. Teng Z. Q. Liu C. M. (2022b). Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development. Development149 (14), dev200049. 10.1242/dev.200049

  • CrossRef
  • Google Scholar

• 20

  Dai X. Lv X. Thompson E. W. Ostrikov K. K. (2022a). Histone lactylation: epigenetic mark of glycolytic switch. Trends Genet.38 (2), 124–127. 10.1016/j.tig.2021.09.009

  • CrossRef
  • Google Scholar

• 21

  De Leo A. Ugolini A. Yu X. Scirocchi F. Scocozza D. Peixoto B. et al (2024). Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity57 (5), 1105–1123 e8. 10.1016/j.immuni.2024.04.006

  • CrossRef
  • Google Scholar

• 22

  Dongre A. Weinberg R. A. (2019). New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol.20 (2), 69–84. 10.1038/s41580-018-0080-4

  • CrossRef
  • Google Scholar

• 23

  Duan W. Liu W. Xia S. Zhou Y. Tang M. Xu M. et al (2023). Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis. J. Transl. Med.21 (1), 547. 10.1186/s12967-023-04403-0

  • CrossRef
  • Google Scholar

• 24

  Elia I. Rowe J. H. Johnson S. Joshi S. Notarangelo G. Kurmi K. et al (2022). Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8(+) T cells. Cell Metab.34 (8), 1137–1150 e6. 10.1016/j.cmet.2022.06.008

  • CrossRef
  • Google Scholar

• 25

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

  • CrossRef
  • Google Scholar

• 26

  Fang X. Zhao P. Gao S. Liu D. Zhang S. Shan M. et al (2023). Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism. Int. J. Biol. Macromol.237, 123810. 10.1016/j.ijbiomac.2023.123810

  • CrossRef
  • Google Scholar

• 27

  Faubert B. Li K. Y. Cai L. Hensley C. T. Kim J. Zacharias L. G. et al (2017). Lactate metabolism in human lung tumors. Cell171 (2), 358–371 e9. 10.1016/j.cell.2017.09.019

  • CrossRef
  • Google Scholar

• 28

  Feng F. Wu J. Chi Q. Wang S. Liu W. Yang L. et al (2024). Lactylome analysis Unveils lactylation-dependent mechanisms of stemness remodeling in the liver cancer stem cells. Adv. Sci. (Weinh)11 (38), e2405975. 10.1002/advs.202405975

  • CrossRef
  • Google Scholar

• 29

  Feng H. Chen W. Zhang C. (2023). Identification of lactylation gene CALML5 and its correlated lncRNAs in cutaneous melanoma by machine learning. Med. Baltim.102 (47), e35999. 10.1097/MD.0000000000035999

  • CrossRef
  • Google Scholar

• 30

  Fu C. Jiang W. Wang C. Song S. J. Tao H. Zhang X. G. et al (2024). AP001885.4 promotes the proliferation of esophageal squamous cell carcinoma cells by histone lactylation- and NF-κB (p65)-dependent transcription activation and METTL3-mediated mRNA stability of c-myc. Anim. Cells Syst. Seoul.28 (1), 536–550. 10.1080/19768354.2024.2417458

  • CrossRef
  • Google Scholar

• 31

  Gaffney D. O. Jennings E. Q. Anderson C. C. Marentette J. O. Shi T. Schou Oxvig A. M. et al (2020). Non-enzymatic lysine Lactoylation of glycolytic enzymes. Cell Chem. Biol.27 (2), 206–213 e6. 10.1016/j.chembiol.2019.11.005

  • CrossRef
  • Google Scholar

• 32

  Gaur P. Prasad S. Kumar B. Sharma S. K. Vats P. (2021). High-altitude hypoxia induced reactive oxygen species generation, signaling, and mitigation approaches. Int. J. Biometeorol.65 (4), 601–615. 10.1007/s00484-020-02037-1

  • CrossRef
  • Google Scholar

• 33

  Gu J. Xu X. Li X. Yue L. Zhu X. Chen Q. et al (2024b). Tumor-resident microbiota contributes to colorectal cancer liver metastasis by lactylation and immune modulation. Oncogene43 (31), 2389–2404. 10.1038/s41388-024-03080-7

  • CrossRef
  • Google Scholar

• 34

  Gu J. Zhou J. Chen Q. Xu X. Gao J. Li X. et al (2022a). Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-beta signaling in regulatory T cells. Cell Rep.39 (12), 110986. 10.1016/j.celrep.2022.110986

  • CrossRef
  • Google Scholar

• 35

  Gu J. Zhou J. Chen Q. Xu X. Gao J. Li X. et al (2022b). Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-beta signaling in regulatory T cells. Cell Rep.40 (3), 111122. 10.1016/j.celrep.2022.111122

  • CrossRef
  • Google Scholar

• 36

  Gu X. Zhuang A. Yu J. Yang L. Ge S. Ruan J. et al (2024a). Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A. Nucleic Acids Res.52 (5), 2273–2289. 10.1093/nar/gkad1193

  • CrossRef
  • Google Scholar

• 37

  Guo Z. Tang Y. Wang S. Huang Y. Chi Q. Xu K. et al (2024). Natural product fargesin interferes with H3 histone lactylation via targeting PKM2 to inhibit non-small cell lung cancer tumorigenesis. Biofactors50 (3), 592–607. 10.1002/biof.2031

  • CrossRef
  • Google Scholar

• 38

  Han J. Won M. Kim J. H. Jung E. Min K. Jangili P. et al (2020). Cancer stem cell-targeted bio-imaging and chemotherapeutic perspective. Chem. Soc. Rev.49 (22), 7856–7878. 10.1039/d0cs00379d

  • CrossRef
  • Google Scholar

• 39

  Han S. Bao X. Zou Y. Wang L. Li Y. Yang L. et al (2023). d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci. Adv.9 (29), eadg2697. 10.1126/sciadv.adg2697

  • CrossRef
  • Google Scholar

• 40

  Hao B. Dong H. Xiong R. Song C. Xu C. Li N. et al (2024). Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma. Comput. Biol. Med.171, 108183. 10.1016/j.compbiomed.2024.108183

  • CrossRef
  • Google Scholar

• 41

  He C. Zhang J. Bai X. Lu C. Zhang K. (2024). Lysine lactylation-based insight to understanding the characterization of cervical cancer. Biochim. Biophys. Acta Mol. Basis Dis.1870 (7), 167356. 10.1016/j.bbadis.2024.167356

  • CrossRef
  • Google Scholar

• 42

  Hirschey M. D. Zhao Y. (2015). Metabolic regulation by lysine Malonylation, Succinylation, and Glutarylation. Mol. Cell Proteomics14 (9), 2308–2315. 10.1074/mcp.R114.046664

  • CrossRef
  • Google Scholar

• 43

  Hou X. Ouyang J. Tang L. Wu P. Deng X. Yan Q. et al (2024). KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation. PLoS Biol.22 (6), e3002666. 10.1371/journal.pbio.3002666

  • CrossRef
  • Google Scholar

• 44

  Huang C. Xue L. Lin X. Shen Y. Wang X. (2024b). Histone lactylation-driven GPD2 mediates M2 macrophage polarization to promote malignant transformation of cervical cancer progression. DNA Cell Biol.43, 605–618. 10.1089/dna.2024.0122

  • CrossRef
  • Google Scholar

• 45

  Huang G. Chen S. He J. Li H. Ma Z. Lubamba G. P. et al (2024c). Histone lysine lactylation (Kla)-induced BCAM promotes OSCC progression and cis-Platinum resistance. Oral Dis.31, 1116–1132. 10.1111/odi.15179

  • CrossRef
  • Google Scholar

• 46

  Huang H. Sabari B. R. Garcia B. A. Allis C. D. Zhao Y. (2014). SnapShot: histone modifications. Cell159 (2), 458–458 e1. 10.1016/j.cell.2014.09.037

  • CrossRef
  • Google Scholar

• 47

  Huang H. Wang S. Xia H. Zhao X. Chen K. Jin G. et al (2024a). Lactate enhances NMNAT1 lactylation to sustain nuclear NAD(+) salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions. Cancer Lett.588, 216806. 10.1016/j.canlet.2024.216806

  • CrossRef
  • Google Scholar

• 48

  Huang Y. Luo G. Peng K. Song Y. Wang Y. Zhang H. et al (2024d). Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity. J. Cell Biol.223 (11), e202308099. 10.1083/jcb.202308099

  • CrossRef
  • Google Scholar

• 49

  Huang Z. W. Zhang X. N. Zhang L. Liu L. L. Zhang J. W. Sun Y. X. et al (2023). STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct. Target Ther.8 (1), 391. 10.1038/s41392-023-01605-2

  • CrossRef
  • Google Scholar

• 50

  Hui S. Ghergurovich J. M. Morscher R. J. Jang C. Teng X. Lu W. et al (2017). Glucose feeds the TCA cycle via circulating lactate. Nature551 (7678), 115–118. 10.1038/nature24057

  • CrossRef
  • Google Scholar

• 51

  Icard P. Shulman S. Farhat D. Steyaert J. M. Alifano M. Lincet H. (2018). How the Warburg effect supports aggressiveness and drug resistance of cancer cells?Drug Resist Updat38, 1–11. 10.1016/j.drup.2018.03.001

  • CrossRef
  • Google Scholar

• 52

  Ippolito L. Morandi A. Giannoni E. Chiarugi P. (2019). Lactate: a metabolic driver in the tumour landscape. Trends Biochem. Sci.44 (2), 153–166. 10.1016/j.tibs.2018.10.011

  • CrossRef
  • Google Scholar

• 53

  Irizarry-Caro R. A. McDaniel M. M. Overcast G. R. Jain V. G. Troutman T. D. Pasare C. (2020). TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc. Natl. Acad. Sci. U. S. A.117 (48), 30628–30638. 10.1073/pnas.2009778117

  • CrossRef
  • Google Scholar

• 54

  Jhunjhunwala S. Hammer C. Delamarre L. (2021). Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat. Rev. Cancer21 (5), 298–312. 10.1038/s41568-021-00339-z

  • CrossRef
  • Google Scholar

• 55

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

  • CrossRef
  • Google Scholar

• 56

  Jiang J. Zheng Q. Zhu W. Chen X. Lu H. Chen D. et al (2020). Alterations in glycolytic/cholesterogenic gene expression in hepatocellular carcinoma. Aging (Albany NY)12 (11), 10300–10316. 10.18632/aging.103254

  • CrossRef
  • Google Scholar

• 57

  Jiang S. Li H. Zhang L. Mu W. Zhang Y. Chen T. et al (2024b). Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Res.53, D1670–D1676. 10.1093/nar/gkae973

  • CrossRef
  • Google Scholar

• 58

  Jiang Z. Xiong N. Yan R. Li S. T. Liu H. Mao Q. et al (2024a). PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation mediated gene expression. Protein Cell16, 49–63. 10.1093/procel/pwae052

  • CrossRef
  • Google Scholar

• 59

  Jiao Y. Ji F. Hou L. Lv Y. Zhang J. (2024). Lactylation-related gene signature for prognostic prediction and immune infiltration analysis in breast cancer. Heliyon10 (3), e24777. 10.1016/j.heliyon.2024.e24777

  • CrossRef
  • Google Scholar

• 60

  Jin M. Cao W. Chen B. Xiong M. Cao G. (2022). Tumor-derived lactate creates a Favorable Niche for tumor via Supplying energy source for tumor and modulating the tumor microenvironment. Front. Cell Dev. Biol.10, 808859. 10.3389/fcell.2022.808859

  • CrossRef
  • Google Scholar

• 61

  Jing F. Zhu L. Zhang J. Zhou X. Bai J. Li X. et al (2024). Multi-omics reveals lactylation-driven regulatory mechanisms promoting tumor progression in oral squamous cell carcinoma. Genome Biol.25 (1), 272. 10.1186/s13059-024-03383-8

  • CrossRef
  • Google Scholar

• 62

  Ju J. Zhang H. Lin M. Yan Z. An L. Cao Z. et al (2024). The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. J. Clin. Invest134 (10), e174587. 10.1172/JCI174587

  • CrossRef
  • Google Scholar

• 63

  Lan J. Luo H. Wu R. Wang J. Zhou B. Zhang Y. et al (2020). Internalization of HMGB1 (high mobility group box 1) promotes angiogenesis in endothelial cells. Arterioscler. Thromb. Vasc. Biol.40 (12), 2922–2940. 10.1161/ATVBAHA.120.315151

  • CrossRef
  • Google Scholar

• 64

  Lei X. Lei Y. Li J. K. Du W. X. Li R. G. Yang J. et al (2020). Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Lett.470, 126–133. 10.1016/j.canlet.2019.11.009

  • CrossRef
  • Google Scholar

• 65

  Li C. Jiang P. Wei S. Xu X. Wang J. (2020). Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol. Cancer19 (1), 116. 10.1186/s12943-020-01234-1

  • CrossRef
  • Google Scholar

• 66

  Li F. Si W. Xia L. Yin D. Wei T. Tao M. et al (2024b). Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Mol. Cancer23 (1), 90. 10.1186/s12943-024-02008-9

  • CrossRef
  • Google Scholar

• 67

  Li F. Zhang H. Huang Y. Li D. Zheng Z. Xie K. et al (2024h). Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer. Drug Resist Updat73, 101059. 10.1016/j.drup.2024.101059

  • CrossRef
  • Google Scholar

• 68

  Li G. Wang D. Zhai Y. Pan C. Zhang J. Wang C. et al (2024). Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma. Cell Metab.36 (8), 1696–1710 e10. 10.1016/j.cmet.2024.07.011

  • CrossRef
  • Google Scholar

• 69

  Li H. Liu C. Li R. Zhou L. Ran Y. Yang Q. et al (2024a). AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases. Nature634 (8036), 1229–1237. 10.1038/s41586-024-07992-y

  • CrossRef
  • Google Scholar

• 70

  Li J. Chen Z. Jin M. Gu X. Wang Y. Huang G. et al (2024c). Histone H4K12 lactylation promotes malignancy progression in triple-negative breast cancer through SLFN5 downregulation. Cell Signal124, 111468. 10.1016/j.cellsig.2024.111468

  • CrossRef
  • Google Scholar

• 71

  Li L. Li Z. Meng X. Wang X. Song D. Liu Y. et al (2023). Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway. Cancer Lett.579, 216467. 10.1016/j.canlet.2023.216467

  • CrossRef
  • Google Scholar

• 72

  Li Q. Lin G. Zhang K. Liu X. Li Z. Bing X. et al (2024d). Hypoxia exposure induces lactylation of Axin1 protein to promote glycolysis of esophageal carcinoma cells. Biochem. Pharmacol.226, 116415. 10.1016/j.bcp.2024.116415

  • CrossRef
  • Google Scholar

• 73

  Li W. Zhou C. Yu L. Hou Z. Liu H. Kong L. et al (2024g). Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy20 (1), 114–130. 10.1080/15548627.2023.2249762

  • CrossRef
  • Google Scholar

• 74

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

  • CrossRef
  • Google Scholar

• 75

  Li X. M. Yang Y. Jiang F. Q. Hu G. Wan S. Yan W. Y. et al (2024f). Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling. Cell Rep.43 (2), 113688. 10.1016/j.celrep.2024.113688

  • CrossRef
  • Google Scholar

• 76

  Li Z. Liang P. Chen Z. Chen Z. Jin T. He F. et al (2024e). CAF-secreted LOX promotes PD-L1 expression via histone Lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric Cancer. Cell Signal124, 111462. 10.1016/j.cellsig.2024.111462

  • CrossRef
  • Google Scholar

• 77

  Liao J. Chen Z. Chang R. Yuan T. Li G. Zhu C. et al (2023). CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1. Int. J. Biol. Sci.19 (16), 5218–5232. 10.7150/ijbs.85656

  • CrossRef
  • Google Scholar

• 78

  Liu J. Chen P. Zhou J. Li H. Pan Z. (2024c). Prognostic impact of lactylation-associated gene modifications in clear cell renal cell carcinoma: insights into molecular landscape and therapeutic opportunities. Environ. Toxicol.39 (3), 1360–1373. 10.1002/tox.24040

  • CrossRef
  • Google Scholar

• 79

  Liu M. Gu L. Zhang Y. Li Y. Zhang L. Xin Y. et al (2024b). LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma. Cancer Lett.595, 217025. 10.1016/j.canlet.2024.217025

  • CrossRef
  • Google Scholar

• 80

  Liu R. Zou Z. Chen L. Feng Y. Ye J. Deng Y. et al (2024a). FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation. Cell Death Dis.15 (1), 64. 10.1038/s41419-024-06450-x

  • CrossRef
  • Google Scholar

• 81

  Lu W. Kang Y. (2019). Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev. Cell49 (3), 361–374. 10.1016/j.devcel.2019.04.010

  • CrossRef
  • Google Scholar

• 82

  Lu X. Zhou Z. Qiu P. Xin T. (2024b). Integrated single-cell and bulk RNA-sequencing data reveal molecular subtypes based on lactylation-related genes and prognosis and therapeutic response in glioma. Heliyon10 (9), e30726. 10.1016/j.heliyon.2024.e30726

  • CrossRef
  • Google Scholar

• 83

  Lu Y. Zhu J. Zhang Y. Li W. Xiong Y. Fan Y. et al (2024a). Lactylation-driven IGF2BP3-mediated serine metabolism reprogramming and RNA m6A-modification promotes Lenvatinib resistance in HCC. Adv. Sci. (Weinh)11, e2401399. 10.1002/advs.202401399

  • CrossRef
  • Google Scholar

• 84

  Luo Y. Yang Z. Yu Y. Zhang P. (2022). HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer. Int. J. Biol. Macromol.222 (Pt B), 2225–2243. 10.1016/j.ijbiomac.2022.10.014

  • CrossRef
  • Google Scholar

• 85

  Meng Q. Sun H. Zhang Y. Yang X. Hao S. Liu B. et al (2024). Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression. J. Exp. Clin. Cancer Res.43 (1), 36. 10.1186/s13046-024-02943-x

  • CrossRef
  • Google Scholar

• 86

  Miao Z. Zhao X. Liu X. (2023). Hypoxia induced beta-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway. Exp. Cell Res.422 (1), 113439. 10.1016/j.yexcr.2022.113439

  • CrossRef
  • Google Scholar

• 87

  Millan-Zambrano G. Burton A. Bannister A. J. Schneider R. (2022). Histone post-translational modifications - cause and consequence of genome function. Nat. Rev. Genet.23 (9), 563–580. 10.1038/s41576-022-00468-7

  • CrossRef
  • Google Scholar

• 88

  Moreno-Yruela C. Bæk M. Monda F. Olsen C. A. (2022a). Chiral Posttranslational modification to lysine epsilon-Amino groups. Acc. Chem. Res.55 (10), 1456–1466. 10.1021/acs.accounts.2c00115

  • CrossRef
  • Google Scholar

• 89

  Moreno-Yruela C. Zhang D. Wei W. Bæk M. Liu W. Gao J. et al (2022b). Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci. Adv.8 (3), eabi6696. 10.1126/sciadv.abi6696

  • CrossRef
  • Google Scholar

• 90

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

  • CrossRef
  • Google Scholar

• 91

  Pan J. Zhang J. Lin J. Cai Y. Zhao Z. (2024). Constructing lactylation-related genes prognostic model to effectively predict the disease-free survival and treatment responsiveness in prostate cancer based on machine learning. Front. Genet.15, 1343140. 10.3389/fgene.2024.1343140

  • CrossRef
  • Google Scholar

• 92

  Pan L. Feng F. Wu J. Fan S. Han J. Wang S. et al (2022). Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharmacol. Res.181, 106270. 10.1016/j.phrs.2022.106270

  • CrossRef
  • Google Scholar

• 93

  Pandkar M. R. Sinha S. Samaiya A. Shukla S. (2023). Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression. Transl. Oncol.37, 101758. 10.1016/j.tranon.2023.101758

  • CrossRef
  • Google Scholar

• 94

  Peng T. Sun F. Yang J. C. Cai M. H. Huai M. X. Pan J. X. et al (2024). Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma. World J. Gastroenterol.30 (19), 2575–2602. 10.3748/wjg.v30.i19.2575

  • CrossRef
  • Google Scholar

• 95

  Qiao Z. Li Y. Li S. Liu S. Cheng Y. (2024). Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells. Mol. Cell Biochem.479 (11), 3063–3076. 10.1007/s11010-023-04913-x

  • CrossRef
  • Google Scholar

• 96

  Raychaudhuri D. Singh P. Chakraborty B. Hennessey M. Tannir A. J. Byregowda S. et al (2024). Histone lactylation drives CD8(+) T cell metabolism and function. Nat. Immunol.25 (11), 2140–2151. 10.1038/s41590-024-01985-9

  • CrossRef
  • Google Scholar

• 97

  Roland C. L. Arumugam T. Deng D. Liu S. H. Philip B. Gomez S. et al (2014). Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res.74 (18), 5301–5310. 10.1158/0008-5472.CAN-14-0319

  • CrossRef
  • Google Scholar

• 98

  Rothbart S. B. Dickson B. M. Strahl B. D. (2015). From histones to ribosomes: a chromatin regulator tangoes with translation. Cancer Discov.5 (3), 228–230. 10.1158/2159-8290.CD-15-0073

  • CrossRef
  • Google Scholar

• 99

  Sabari B. R. Zhang D. Allis C. D. Zhao Y. (2017). Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol.18 (2), 90–101. 10.1038/nrm.2016.140

  • CrossRef
  • Google Scholar

• 100

  Sun L. Zhang Y. Yang B. Sun S. Zhang P. Luo Z. et al (2023c). Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer. Nat. Commun.14 (1), 6523. 10.1038/s41467-023-42025-8

  • CrossRef
  • Google Scholar

• 101

  Sun T. Liu B. Li Y. Wu J. Cao Y. Yang S. et al (2023d). Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation. J. Exp. Clin. Cancer Res.42 (1), 253. 10.1186/s13046-023-02815-w

  • CrossRef
  • Google Scholar

• 102

  Sun W. Jia M. Feng Y. Cheng X. (2023b). Lactate is a bridge linking glycolysis and autophagy through lactylation. Autophagy19 (12), 3240–3241. 10.1080/15548627.2023.2246356

  • CrossRef
  • Google Scholar

• 103

  Sun X. He L. Liu H. Thorne R. F. Zeng T. Liu L. et al (2023a). The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity. Cell Metab.35 (9), 1563–1579 e8. 10.1016/j.cmet.2023.07.005

  • CrossRef
  • Google Scholar

• 104

  Takata T. Nakamura A. Yasuda H. Miyake H. Sogame Y. Sawai Y. et al (2024). Pathophysiological implications of protein lactylation in pancreatic epithelial tumors. Acta Histochem Cytochem57 (2), 57–66. 10.1267/ahc.24-00010

  • CrossRef
  • Google Scholar

• 105

  Wan N. Wang N. Yu S. Zhang H. Tang S. Wang D. et al (2022). Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome. Nat. Methods19 (7), 854–864. 10.1038/s41592-022-01523-1

  • CrossRef
  • Google Scholar

• 106

  Wang D. Du G. Chen X. Wang J. Liu K. Zhao H. et al (2024b). Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer. Cell Death Differ.31 (6), 779–791. 10.1038/s41418-024-01295-5

  • CrossRef
  • Google Scholar

• 107

  Wang H. Xu M. Zhang T. Pan J. Li C. Pan B. et al (2024a). PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification. Clin. Transl. Med.14 (10), e70045. 10.1002/ctm2.70045

  • CrossRef
  • Google Scholar

• 108

  Wang J. Liu Z. Xu Y. Wang Y. Wang F. Zhang Q. et al (2022c). Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration. Front. Cell Infect. Microbiol.12, 913815. 10.3389/fcimb.2022.913815

  • CrossRef
  • Google Scholar

• 109

  Wang J. Yang P. Yu T. Gao M. Liu D. Zhang J. et al (2022a). Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int. J. Biol. Sci.18 (16), 6210–6225. 10.7150/ijbs.75434

  • CrossRef
  • Google Scholar

• 110

  Wang L. Li S. Luo H. Lu Q. Yu S. (2022b). PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J. Exp. Clin. Cancer Res.41 (1), 303. 10.1186/s13046-022-02477-0

  • CrossRef
  • Google Scholar

• 111

  Wang M. He T. Meng D. Lv W. Ye J. Cheng L. et al (2023a). BZW2 modulates lung adenocarcinoma progression through glycolysis-mediated IDH3G lactylation modification. J. Proteome Res.22 (12), 3854–3865. 10.1021/acs.jproteome.3c00518

  • CrossRef
  • Google Scholar

• 112

  Wang N. Jiang X. Zhang S. Zhu A. Yuan Y. Xu H. et al (2021b). Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell184 (2), 370–383 e13. 10.1016/j.cell.2020.11.043

  • CrossRef
  • Google Scholar

• 113

  Wang R. Li C. Cheng Z. Li M. Shi J. Zhang Z. et al (2024c). H3K9 lactylation in malignant cells facilitates CD8(+) T cell dysfunction and poor immunotherapy response. Cell Rep.43 (9), 114686. 10.1016/j.celrep.2024.114686

  • CrossRef
  • Google Scholar

• 114

  Wang X. Ying T. Yuan J. Wang Y. Su X. Chen S. et al (2023b). BRAFV600E restructures cellular lactylation to promote anaplastic thyroid cancer proliferation. Endocr. Relat. Cancer30 (8), e220344. 10.1530/ERC-22-0344

  • CrossRef
  • Google Scholar

• 115

  Wang Z. H. Peng W. B. Zhang P. Yang X. P. Zhou Q. (2021a). Lactate in the tumour microenvironment: from immune modulation to therapy. EBioMedicine73, 103627. 10.1016/j.ebiom.2021.103627

  • CrossRef
  • Google Scholar

• 116

  Warburg O. Wind F. Negelein E. (1927). The metabolism of tumors in the Body. J. Gen. Physiol.8 (6), 519–530. 10.1085/jgp.8.6.519

  • CrossRef
  • Google Scholar

• 117

  Wu X. Mi T. Jin L. Ren C. Wang J. Zhang Z. et al (2024b). Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma. Cancer Immunol. Immunother.73 (7), 122. 10.1007/s00262-024-03702-9

  • CrossRef
  • Google Scholar

• 118

  Wu Z. Wu H. Dai Y. Wang Z. Han H. Shen Y. et al (2024a). A pan-cancer multi-omics analysis of lactylation genes associated with tumor microenvironment and cancer development. Heliyon10 (5), e27465. 10.1016/j.heliyon.2024.e27465

  • CrossRef
  • Google Scholar

• 119

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

  • CrossRef
  • Google Scholar

• 120

  Xiong J. He J. Zhu J. Pan J. Liao W. Ye H. et al (2022). Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol. Cell82 (9), 1660–1677 e10. 10.1016/j.molcel.2022.02.033

  • CrossRef
  • Google Scholar

• 121

  Xu H. Li L. Wang S. Wang Z. Qu L. Wang C. et al (2023). Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine118, 154940. 10.1016/j.phymed.2023.154940

  • CrossRef
  • Google Scholar

• 122

  Yang D. Yin J. Shan L. Yi X. Zhang W. Ding Y. (2022b). Identification of lysine-lactylated substrates in gastric cancer cells. iScience25 (7), 104630. 10.1016/j.isci.2022.104630

  • CrossRef
  • Google Scholar

• 123

  Yang H. Yang S. He J. Li W. Zhang A. Li N. et al (2023a). Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer. Cancer Cell Int.23 (1), 303. 10.1186/s12935-023-03162-8

  • CrossRef
  • Google Scholar

• 124

  Yang H. Zou X. Yang S. Zhang A. Ma Z. (2023b). Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front. Immunol.14, 1149989. 10.3389/fimmu.2023.1149989

  • CrossRef
  • Google Scholar

• 125

  Yang K. Fan M. Wang X. Xu J. Wang Y. Tu F. et al (2022a). Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ.29 (1), 133–146. 10.1038/s41418-021-00841-9

  • CrossRef
  • Google Scholar

• 126

  Yang Z. Yan C. Ma J. Peng P. Ren X. Cai S. et al (2023). Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat. Metab.5 (1), 61–79. 10.1038/s42255-022-00710-w

  • CrossRef
  • Google Scholar

• 127

  Yao G. Yang Z. (2024). Glypican-3 knockdown inhibits the cell growth, stemness, and glycolysis development of hepatocellular carcinoma cells under hypoxic microenvironment through lactylation. Arch. Physiol. Biochem.130 (5), 546–554. 10.1080/13813455.2023.2206982

  • CrossRef
  • Google Scholar

• 128

  Ye J. Gao X. Huang X. Huang S. Zeng D. Luo W. et al (2024). Integrating single-cell and spatial transcriptomics to uncover and elucidate GP73-mediated pro-angiogenic regulatory Networks in hepatocellular carcinoma. Research (Wash D C)7, 0387. 10.34133/research.0387

  • CrossRef
  • Google Scholar

• 129

  Yin X. Xing W. Yi N. Zhou Y. Chen Y. Jiang Z. et al (2024). Comprehensive analysis of lactylation-related gene sets and mitochondrial functions in gastric adenocarcinoma: implications for prognosis and therapeutic strategies. Front. Immunol.15, 1451725. 10.3389/fimmu.2024.1451725

  • CrossRef
  • Google Scholar

• 130

  Yu J. Chai P. Xie M. Ge S. Ruan J. Fan X. et al (2021). Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol.22 (1), 85. 10.1186/s13059-021-02308-z

  • CrossRef
  • Google Scholar

• 131

  Yu L. Jing C. Zhuang S. Ji L. Jiang L. (2024). A novel lactylation-related gene signature for effectively distinguishing and predicting the prognosis of ovarian cancer. Transl. Cancer Res.13 (5), 2497–2508. 10.21037/tcr-24-319

  • CrossRef
  • Google Scholar

• 132

  Yuan X. Wang Q. Zhao J. Xie H. Pu Z. (2024). The m6A methyltransferase METTL3 modifies Kcnk6 promoting on inflammation associated carcinogenesis is essential for colon homeostasis and defense system through histone lactylation dependent YTHDF2 binding. Int. Rev. Immunol.44, 1–16. 10.1080/08830185.2024.2401358

  • CrossRef
  • Google Scholar

• 133

  Yue Q. Wang Z. Shen Y. Lan Y. Zhong X. Luo X. et al (2024). Histone H3K9 lactylation confers Temozolomide resistance in glioblastoma via LUC7L2-mediated MLH1 Intron Retention. Adv. Sci. (Weinh)11 (19), e2309290. 10.1002/advs.202309290

  • CrossRef
  • Google Scholar

• 134

  Zang Y. Wang A. Zhang J. Xia M. Jiang Z. Jia B. et al (2024). Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma. iScience27 (7), 110188. 10.1016/j.isci.2024.110188

  • CrossRef
  • Google Scholar

• 135

  Zeng Q. Wang K. Zhao Y. Ma Q. Chen Z. Huang W. (2023). Effects of the acetyltransferase p300 on tumour regulation from the novel perspective of Posttranslational protein modification. Biomolecules13 (3), 417. 10.3390/biom13030417

  • CrossRef
  • Google Scholar

• 136

  Zhang C. Zhou L. Zhang M. Du Y. Li C. Ren H. et al (2024b). H3K18 lactylation potentiates immune Escape of non-small cell lung cancer. Cancer Res.84 (21), 3589–3601. 10.1158/0008-5472.CAN-23-3513

  • CrossRef
  • Google Scholar

• 137

  Zhang D. Tang Z. Huang H. Zhou G. Cui C. Weng Y. et al (2019). Metabolic regulation of gene expression by histone lactylation. Nature574 (7779), 575–580. 10.1038/s41586-019-1678-1

  • CrossRef
  • Google Scholar

• 138

  Zhang R. Li L. Yu J. (2024a). Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells. Open Life Sci.19 (1), 20220874. 10.1515/biol-2022-0874

  • CrossRef
  • Google Scholar

• 139

  Zhao P. Qiao C. Wang J. Zhou Y. Zhang C. (2024c). Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression. Mol. Carcinog.63 (11), 2078–2089. 10.1002/mc.23794

  • CrossRef
  • Google Scholar

• 140

  Zhao R. Yi Y. Liu H. Xu J. Chen S. Wu D. et al (2024b). RHOF promotes Snail1 lactylation by enhancing PKM2-mediated glycolysis to induce pancreatic cancer cell endothelial-mesenchymal transition. Cancer Metab.12 (1), 32. 10.1186/s40170-024-00362-2

  • CrossRef
  • Google Scholar

• 141

  Zhao Y. Jiang J. Zhou P. Deng K. Liu Z. Yang M. et al (2024a). H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem. Pharmacol.222, 116120. 10.1016/j.bcp.2024.116120

  • CrossRef
  • Google Scholar

• 142

  Zheng P. Mao Z. Luo M. Zhou L. Wang L. Liu H. et al (2023). Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma. Cancer Cell Int.23 (1), 222. 10.1186/s12935-023-03082-7

  • CrossRef
  • Google Scholar

• 143

  Zheng Y. Yang Y. Xiong Q. Ma Y. Zhu Q. (2024). Establishment and Verification of a novel gene signature connecting hypoxia and lactylation for predicting prognosis and immunotherapy of pancreatic ductal adenocarcinoma patients by integrating multi-machine learning and single-cell analysis. Int. J. Mol. Sci.25 (20), 11143. 10.3390/ijms252011143

  • CrossRef
  • Google Scholar

• 144

  Zhou C. Li W. Liang Z. Wu X. Cheng S. Peng J. et al (2024). Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death. Nat. Commun.15 (1), 499. 10.1038/s41467-024-44779-1

  • CrossRef
  • Google Scholar

• 145

  Zhou J. Xu W. Wu Y. Wang M. Zhang N. Wang L. et al (2023). GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. Oncogene42 (45), 3319–3330. 10.1038/s41388-023-02841-0

  • CrossRef
  • Google Scholar

• 146

  Zhu J. Zhang Y. (2024). Dexmedetomidine inhibits the migration, invasion, and glycolysis of glioblastoma cells by lactylation of c-myc. Neurol. Res.46, 1105–1112. 10.1080/01616412.2024.2395069

  • CrossRef
  • Google Scholar

• 147

  Zong Z. Xie F. Wang S. Wu X. Zhang Z. Yang B. et al (2024). Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell187 (10), 2375–2392 e33. 10.1016/j.cell.2024.04.002

  • CrossRef
  • Google Scholar