When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease

Given that comprehensive reviews have extensively summarized the epigenetic regulation of metabolic enzyme expression and its pathophysiological significance, this paper will not elaborate further on these topics. Instead, we focus on how lactylation modification alters the intrinsic properties of metabolic enzymes. Although Section 3 discusses lactylation of individual metabolic enzymes in detail, this section revisits these findings and provides a brief classification and summary of the properties of metabolic enzymes that are altered by this modification. Specifically, lactylation modulates catalytic activity, influences protein degradation, and mediates enzyme-molecule interactions ( Figure 5 ; Table 1 ). Lactylation affects the properties of metabolic enzymes. Lactylation of metabolic enzymes alters their functional properties. These changes manifest in three ways: modulation of enzyme activity either enhancing or reducing it, alteration of protein degradation, and regulation of interactions between proteins and other molecules. Created with BioRender.com . Emerging evidence indicates that lactylation exerts a bidirectional regulatory effect on metabolic enzyme activity, functioning as either an inhibitor or an activator depending on the specific enzyme and the cellular context. For a range of metabolic enzymes, lactylation serves as an inhibitory modification. In glucose metabolism, lactylation at K688 of PFKP inhibits its activity, potentially suppressing colorectal cancer progression ( Cheng et al., 2024 ). ALDOA undergoes lactylation at K147, a residue critical for substrate binding, resulting in diminished enzymatic function ( Wan et al., 2022 ; Cheng et al., 2024 ). Lactylation of PDHA1 at K336 by AARS2 inhibits its activity, which in turn shifts the metabolic balance toward glycolysis ( Mao et al., 2024 ). In the TCA cycle, lactylation of CS at K370 inhibits its enzymatic activity, ultimately leading to kidney injury ( Yu et al., 2025 ). G6PD and 6PGD undergo lactylation at K432 and K38, respectively, with both modifications inhibiting their enzymatic activities and thereby potentially protecting the intestinal mucosal barrier ( Wu et al., 2026 ). Furthermore, lactylation of UGDH at K6 reduces its enzymatic activity, and ultimately exacerbates osteoarthritis ( Lan et al., 2025 ). In lipid metabolism, lactylation similarly exerts inhibitory effects. ACLY activity is inhibited by lactylation at K918/K995, compromising metabolic activity and attenuating inflammatory responses ( Zhang Y. et al., 2024 ). FASN is subject to lactylation at K673, which inhibits fatty acid synthesis ( Gao et al., 2023 ). CPT2 undergoes lactylation at K457/K458, which inhibits its enzymatic activity, thereby suppressing OXPHOS ( Zhou F. et al., 2025 ). Lactylation of HADHA at K166/K728 impairs its enzymatic activity, thereby contributing to sepsis-induced cardiac dysfunction ( Zhang T. N. et al., 2025 ). In membrane lipid metabolism, lactylation of LPCAT2 at K375 reduces its acetyltransferase enzymatic activity, inducing ferroptosis and contributing to the progression of sepsis-induced acute lung injury ( Deng et al., 2026 ). In amino acid metabolism, the serine-metabolizing enzyme PHGDH undergoes lactylation at multiple sites (K21, K69, K289, and K394). This modification potentially inhibits its enzymatic activity and potentially impairs intracellular serine synthesis ( Trujillo et al., 2025 ). Within nucleotide homeostasis, lactylation of AK2 at K28 impairs its enzymatic function, thereby potentially promoting the proliferation and metastasis of hepatocellular carcinoma cells ( Yang Z. et al., 2023 ). In contrast to the inhibitory effects described above, lactylation can also enhance the catalytic activity of several metabolic enzymes. In glucose metabolism, lactylation at K346 of HK2 enhances its enzymatic activity, contributing to the pathogenesis of preeclampsia (PE) ( Chen Z. et al., 2025 ). PGAM1 undergoes lactylation at K251, which enhances its enzymatic activity, and ultimately promotes the progression of hepatocellular carcinoma ( Li Q. et al., 2026 ). PKM2 undergoes lactylation at K62, which enhances its enzymatic activity and suppresses inflammatory responses ( Wang et al., 2022 ). LDHA is activated by lactylation at K81 and K318, leading to increased intracellular lactate levels and resistance to cisplatin ( Li J. et al., 2026 ). MDH2 exhibits enhanced enzymatic activity following K239 lactylation, which remodels mitochondrial metabolism and accelerates renal cancer progression ( Tang et al., 2025 ). PCK2 shows increased activity after K100 lactylation, ultimately leading to liver injury ( Yuan et al., 2025 ). The effect of lactylation on G6PD is context-dependent. Lactylation at K45-47 enhances G6PD activity. In C33A cells infected with HPV16, however, G6PD activity is increased only when K45 lactylation is blocked, leading to promotion of the malignant phenotypes in tumor cells ( Meng et al., 2024b ; Zhang Y. et al., 2025 ). In lipid metabolism, lactylation at K412 of ACSL4 enhances its enzymatic activity, thereby promoting ferroptosis ( Sun K. et al., 2025 ). ACAA2 exhibits enhanced catalytic activity following K214 lactylation, contributing to triple-negative breast cancer progression ( Cui et al., 2025 ). ME2, which supplies NADPH for lipid metabolism, shows increased catalytic activity after K352 lactylation, promoting tumor progression ( Li C. et al., 2025 ). VPS34 lactylation at K356 and K781 enhances its binding to Beclin1, ATG14L, and UVRAG, promoting its lipokinase activity and autophagosome formation/maturation ( Jia et al., 2023 ). In amino acid metabolism, specifically the glutathione metabolic pathway, GCLM enhances GCL activity through its lactylation at K34, inducing resistance to ferroptosis in KRAS G12D mutant cancer cells ( Chen Y. et al., 2025 ). Finally, in nucleotide metabolism, NDPK undergoes lactylation at K49, which enhances its enzymatic activity and promotes the synthesis of nucleotides and deoxyribonucleotides ( Batsios et al., 2026 ). Beyond modulating catalytic activity, lactylation also affects the degradation of metabolic enzymes, thereby influencing their stability. Notably, the same enzyme can exhibit distinct functional outcomes depending on which residue is lactylated. In glucose metabolism, PFKP provides a clear example of this site-specific effect. As discussed in Section 5.1.1 , lactylation at K688 of PFKP inhibits its enzymatic activity ( Cheng et al., 2024 ). However, when lactylation occurs at a different residue, K392, it produces an opposing effect. Lactylation at K392 inhibits PFKP degradation, thereby promoting ovarian cancer progression ( Mi et al., 2025 ). Similarly, lactylation at K11 of PGK1 in A549 cells enhances its protein stability and protects it from degradation ( Wan et al., 2022 ). Interestingly, lactylation at a single residue can exert dual regulatory effects by simultaneously enhancing enzymatic activity and protein stability. PGAM1 undergoes competitive lactylation and ubiquitination at K251. Lactylation at this site suppresses ubiquitination, thereby preventing ubiquitin–proteasome-mediated degradation and enhancing protein stability ( Li Q. et al., 2026 ). Notably, lactylation of certain metabolic enzymes regulates protein stability alone, without altering their enzymatic activity. Lactylation of GPI at K454 also enhances its stability, potentially exacerbating rheumatoid arthritis ( Tan et al., 2025 ). Within glycerophospholipid catabolism, PLBD1 undergoes lactylation at K155. This post-translational modification enhances PLBD1 stability, thereby contributing to exacerbated brain damage following ischemic stroke ( Zhou F. et al., 2025 ). Of note, although lactylation appears to predominantly enhance metabolic enzyme stability by inhibiting ubiquitination, this is not a universal rule. A recent study has demonstrated that the lactylation of GPX4 at K218 and K228 reduces its protein stability, ultimately promoting cardiomyocyte ferroptosis ( Wang Y. et al., 2025 ). Lactylation of cGAS at K21, induced by accumulated lactate, facilitates its translocation to the proteasome for degradation, representing a distinct mechanism that promotes protein decay ( Rao et al., 2025 ). Beyond altering enzyme activity and stability, lactylation can also influence the capacity of metabolic enzymes to interact with other biomolecules, including proteins and RNA. Emerging evidence indicates that such modifications can either promote or disrupt these interactions, thereby exerting diverse functional consequences. Several studies have demonstrated that lactylation affects protein-protein interactions involving metabolic enzymes. In glucose metabolism, lactylation of ALDOA at K230 and K322 inhibits its binding to DDX17, thereby potentially maintaining tumor stemness ( Feng et al., 2024 ). Lactylation of PGK1 at K361 regulates its interaction with VDAC3, potentially contributing to mitochondrial damage and ferroptosis ( Qin et al., 2026 ). ENO1 undergoes lactylation at K89, which enhances its interaction with metabolic enzymes such as PKM1, PKM2, and LDHB, and eventually accelerating resistance to osimertinib ( Gan et al., 2026 ). PKM2 is subject to lactylation at K206, which promotes its nuclear translocation and interaction with FOSL1, ultimately facilitating vascular mimicry in colorectal cancer and conferring resistance to bevacizumab ( Li W. et al., 2026 ). Lactylation of MDH2 at K239 strengthens the interaction between MDH2 and the citrate transporter SLC25A1, ultimately promoting renal cell carcinoma progression ( Tang et al., 2025 ). IDH2, when lactylated at K272, facilitates its binding to caveolin-1, eventually improving cardiac repair following diabetic myocardial infarction ( Zang et al., 2025 ). Lactylation of VPS34 at K356 and K781 enhances its binding to Beclin1, ATG14L, and UVRAG, thereby contributing to autophagosome formation and maturation ( Jia et al., 2023 ). Xie et al. reported that elevated lactate levels during sepsis promote lactylation of ENO1 at K71, an event facilitated by increased activity of the lactyltransferase p300. This modification reduces the binding of ENO1 to TRIM21 mRNA, thereby preventing its degradation by limiting the recruitment of CNOT6 ( Xie et al., 2026 ). Together, these examples illustrate that lactylation not only influences the interplay between catalytic and RNA-binding functions of metabolic enzymes but also expands their regulatory repertoire beyond classical control, enabling dynamic interactions with diverse molecular partners.

Lactic acid was first discovered in 1780 by Carl Wilhelm Scheele in sour milk ( Kompanje et al., 2007 ). It is a three-carbon organic acid primarily generated from pyruvate via lactate dehydrogenase (LDH), and is subsequently transported across cell membranes by monocarboxylate transporters (MCTs) ( Brooks, 1986 ). For decades, lactate was long regarded as a metabolic waste ( Gladden, 2004 ). However, emerging evidence over the past two decades has reshaped this view, revealing that lactate serves as a critical energy substrate, a gluconeogenic precursor, a cellular redox buffer, a metabolic signaling molecule, an epigenetic regulator, and a modulator of immune and inflammatory responses ( Hui et al., 2017 ; Li et al., 2022 ; Yang et al., 2022 ; Hensel et al., 2025 ; Llibre et al., 2025 ). Despite this progress, the molecular mechanisms underlying lactate’s other functions remain largely unclear. The discovery of lysine lactylation (Kla) in 2019 provided a pivotal mechanistic breakthrough ( Zhang et al., 2019 ). Identified initially on histones, lactylation was shown to regulate gene transcription. Since then, a growing number of “writers,” “erasers,” and potential “readers” of lactylation have been characterized ( Zong et al., 2025 ; Sheng et al., 2026 ). Beyond histones, lactylation has been found to occur on non-histone proteins, where it regulates diverse protein properties including enzymatic activity, stability, subcellular localization, and interactions with other molecules ( Zhang et al., 2023 ; Huang Y. et al., 2024 ; Meng et al., 2024a ; Zeng et al., 2025 ; Huang et al., 2026 ). These findings position lactylation as a novel post-translational modification linking lactate to diverse physiopathological processes, such as exercise, neuronal activity, tissue injury, infection, inflammation, aging, cancer, metabolic disorders, cardiovascular diseases, and degenerative diseases ( Han et al., 2023 ; Hu Y. et al., 2024 ; Qiao et al., 2024 ; Yan et al., 2024 ; Zhu et al., 2024 ; Liu et al., 2025d ; Deng et al., 2026 ). Lactylation is a distinctive post-translational modification (PTM) among the expanding repertoire of protein modifications, as it directly links intracellular lactate metabolism with protein regulation. In turn, lactylation regulates metabolism by modulating metabolic enzyme activity, metabolic gene expression, and metabolism-related signaling, forming a reciprocal regulatory loop ( Liu J. et al., 2025 ; Huang et al., 2026 ; Li J. et al., 2026 ). Previous reviews have primarily focused on the mechanisms and biological functions of lactylation, or have explored its relationship with metabolic reprogramming from a largely unidirectional perspective ( Chen et al., 2021 ; Liu et al., 2022 ; Yang J. et al., 2025 ). In contrast, this review summarizes recent advances in the reciprocal interplay between cellular metabolism and protein lactylation ( Figure 1 ), with a particular focus on metabolic enzymes as both regulators and targets of lactylation. We emphasize how metabolic enzymes influence lactylation through their roles in lactate production, as well as how lactylation, in turn, regulates metabolic enzyme function and alters metabolic pathways. We also discuss the roles of this regulatory network in human diseases, current challenges, future directions, and the therapeutic potential of targeting metabolic enzyme lactylation. Lactylation-mediated feedback regulatory loop of glycolysis. Glycolysis drives lactate production, which in turn promotes the lactylation of both histone and non-histone proteins. Histone lactylation modulates the transcription of metabolic enzymes and other proteins, whereas non-histone lactylation can be divided into lactylation of metabolic enzymes and lactylation of other proteins. Histone lactylation regulates the expression levels of various proteins, which, together with the lactylation of non-metabolic enzymes, coordinately influences the abundance and activity of metabolic enzymes, thereby feeding back to regulate glycolysis. Additionally, direct lactylation of metabolic enzymes can alter their enzymatic activities and functional properties, further modulating glycolytic flux. This multilayered interplay between lactylation and glycolysis constitutes a self-regulating feedback loop. Created with BioRender.com .

Since the discovery of protein lactylation in 2019 ( Zhang et al., 2019 ), this lactate-derived post-translational modification has emerged as a cutting-edge research frontier in biology. Lactylation alters protein conformation, charge, and molecular interactions, thereby modulating key protein properties including enzymatic activity, stability, subcellular localization, and binding capacity. At the molecular level, these changes enable lactylation to regulate a broad spectrum of biological processes, such as gene expression, cellular metabolism, signal transduction, and programmed cell death. Consequently, lactylation is implicated in the pathogenesis of various diseases, including cancer, inflammatory disorders, cardiovascular diseases, and neurodegenerative diseases ( Figure 6 ). In this review, we systematically summarized the reciprocal metabolic–lactylation feedback loop and highlighted how lactylation regulates metabolic enzyme properties, including catalytic activity, protein stability, and molecular interactions ( Figure 5 ; Table 1 ). A recurring theme is that lactylation exerts bidirectional effects on enzyme function—either activating or inhibiting—depending on the specific enzyme, the modified residue, and the cellular context. Notably, the same enzyme can exhibit opposing functional outcomes when lactylated at different sites ( Cheng et al., 2024 ; Mi et al., 2025 ; Gan et al., 2026 ; Xie et al., 2026 ). These observations underscore the importance of site-specific analysis in future studies. Previous analysis revealed that the number of lactylated proteins was far lower in normal cells than in tumor cells ( Yang Y. H. et al., 2023 ), suggesting that aberrant lactylation may serve as a hallmark of metabolic rewiring in cancer—a notion consistent with the Warburg effect. This observation points to a bidirectional interplay between metabolic enzymes and lactylation. On one hand, metabolic enzymes control lactate production and thereby shape the lactylation landscape. On the other hand, lactylation exerts feedback regulation through two mechanisms. Directly, lactylation of metabolic enzymes per se alters their intrinsic properties, including activity, stability, and interactions. Indirectly, lactylation modulates the expression or activity of metabolic enzymes via two routes: histone lactylation epigenetically regulates the transcription of metabolic enzymes, while lactylation of other proteins affects the expression or activity of metabolic enzymes. Mass spectrometry-based identification across several tumor types has revealed eight metabolic enzymes that undergo lactylation in multiple cancers, six of which are closely linked to glucose metabolism. Beyond glucose metabolism, enzymes involved in lipid, nucleotide, and amino acid metabolism are also highly lactylated, further emphasizing the pervasive interplay between this modification and cellular metabolism. Despite these advances, several fundamental questions remain unanswered: Beyond Activity and Stability: Multi-dimensional Regulation of Metabolic Enzymes by Lactylation Beyond Activity and Stability: Multi-dimensional Regulation of Metabolic Enzymes by Lactylation Current research has predominantly focused on how lactylation affects the catalytic activity and protein stability of metabolic enzymes. However, lactylation may also regulate metabolic enzymes through additional mechanisms, including altering subcellular localization, modulating substrate specificity, and affecting interactions with other metabolic enzymes or signaling molecules. Systematic investigation of these multi-dimensional regulatory effects will be essential for a comprehensive understanding of how lactylation controls metabolic enzyme function. Dynamic Regulation of Metabolic Enzyme Lactylation in Response to Metabolic States Dynamic Regulation of Metabolic Enzyme Lactylation in Response to Metabolic States Metabolic enzymes both control lactate production and serve as substrates for lactylation, creating a potential feedback circuit. How metabolic enzyme lactylation dynamically changes under different metabolic states—such as glycolysis-dominant versus oxidative phosphorylation-dominant conditions—remains unclear. Similarly, whether metabolic enzymes in distinct subcellular compartments exhibit differential lactylation patterns warrants investigation. Development of sensitive detection tools, including lactylation site-specific antibodies, will be critical for addressing these questions. Limitations in Understanding the Specificity of Lactylation Writers and Erasers Limitations in Understanding the Specificity of Lactylation Writers and Erasers Although previous studies have reported that several proteins exhibit lactylation “writer” or “eraser” activities, the molecular mechanisms governing lactylation regulation and the enzymatic specificity of these regulatory factors remain incompletely understood. In particular, their substrate preferences, the experimental evidence supporting site-specific regulation, and the extent to which their activities are influenced by cellular metabolic states and microenvironmental conditions require further investigation. Moreover, whether protein lactylation is regulated in a compartment-specific manner according to subcellular localization or local metabolic environments remains largely unexplored. Future studies should focus on systematically defining the substrate selectivity of lactylation writers and erasers, while developing precise site-specific detection and editing technologies to further elucidate their regulatory mechanisms and biological functions. Crosstalk Between Lactylation and Other Post-Translational Modifications on Metabolic Enzymes Crosstalk Between Lactylation and Other Post-Translational Modifications on Metabolic Enzymes Metabolic enzymes are regulated by diverse PTMs, including acetylation, succinylation, and ubiquitination. As a recently identified PTM, lactylation remains less understood in terms of its molecular mechanisms and structural basis. Emerging evidence suggests that lactylation may crosstalk with other PTMs; for example, it may compete with ubiquitination for lysine residues. Given that many lactylation regulators also control acetylation, potential competition between lactylation and acetylation may exist. Moreover, the reported generation of lactyl-CoA and succinyl-CoA by GTPSCS suggests possible crosstalk between lactylation and succinylation. Future studies should further define these PTM interactions. In vivo Functional Validation: The Scarcity of Metabolic Enzyme Lactylation Knockin Mouse Models In vivo Functional Validation: The Scarcity of Metabolic Enzyme Lactylation Knockin Mouse Models The vast majority of lactylation functional studies rely on cell-based systems or in vitro experiments, leaving the in vivo physiological and pathological significance of metabolic enzyme lactylation largely undefined. Systematic generation of lactylation-deficient or lactylation-mimetic knockin mice targeting specific metabolic enzyme sites is urgently needed. Large-Scale Lactylomics Analysis: Systematic Comparison of Metabolic Enzyme Lactylation Profiles Between Tumor and Normal Tissues Large-Scale Lactylomics Analysis: Systematic Comparison of Metabolic Enzyme Lactylation Profiles Between Tumor and Normal Tissues Lactylomics studies have identified thousands of lactylation sites across multiple cancer types, with metabolic enzymes consistently enriched among the modified proteins. However, systematic comparisons of metabolic enzyme lactylation profiles between tumor and normal tissues remain in their early stages. Future efforts should focus on constructing comprehensive “tumor metabolic enzyme lactylation atlases” to identify cancer-specific lactylation events with diagnostic or therapeutic potential. Methodological Limitations of Current Research Methods for Lactylation Methodological Limitations of Current Research Methods for Lactylation Current lactylation research faces several challenges, including limited antibody specificity, insufficient discrimination between D- and L-lactylation by mass spectrometry, and inadequate validation of modification sites. Moreover, the lack of site-specific editing tools and structural analyses limits our understanding of how lactylation regulates protein function. Current studies mainly rely on K→Q mutations or computational predictions, whereas direct structural evidence remains scarce. Future research should integrate advanced detection and editing technologies with high-resolution approaches, such as cryo-electron microscopy and X-ray crystallography, to define lactylation sites and elucidate their effects on protein conformation, interactions, and enzymatic activity. Context-Dependent Roles of Lactylation in Disease Progression Context-Dependent Roles of Lactylation in Disease Progression Due to the increasing number of studies investigating the association between lactylation and disease, lactylation is often perceived as a disease-promoting modification. However, lactylation is not exclusively associated with pathological progression and may exert context-dependent effects. In cancer, the Warburg effect leads to elevated intracellular lactate levels, which can increase global lactylation and potentially reflect a metabolic adaptation response of tumor cells. Nevertheless, increased lactylation does not necessarily promote tumor progression, and certain lactylation events may even exert tumor-suppressive effects. Further studies are required to elucidate the diverse and context-specific roles of lactylation in disease development. Therapeutic Strategies Targeting Metabolic Enzyme Lactylation Therapeutic Strategies Targeting Metabolic Enzyme Lactylation Given that lactylation levels are significantly elevated in tumor cells and contribute to metabolic reprogramming and chemotherapy resistance, targeting specific lactylation events on metabolic enzymes may represent a novel therapeutic strategy. Structure-based inhibitors or PROTAC technology could be developed to target aberrantly lactylated metabolic enzymes. In summary, lactylation of metabolic enzymes represents a rapidly growing field that bridges metabolism and post-translational regulation. A deeper understanding of its mechanisms and functions will not only illuminate fundamental biological principles but also open new avenues for therapeutic intervention in cancer, inflammatory diseases, and beyond.

Lactylation is a metabolism-derived post-translational modification that depends on lactate as its substrate. Given that lactate is primarily produced through glycolysis, cellular lactylation levels are intimately linked to glucose metabolism. Indeed, fluctuations in glycolytic flux directly influence the availability of lactate, thereby shaping the global lactylation landscape. Consequently, glucose metabolism serves as a critical regulator of both histone and non-histone lactylation. Metabolic enzymes play a central role in this regulatory axis by controlling the rate of lactate production. Enzymes such as phosphofructokinase (PFK), PKM2, and LDHA determine glycolytic output and, in turn, the intracellular concentration of lactate. As such, these enzymes function as key determinants of the lactylation landscape within cells. By modulating lactate availability, they indirectly govern the lactylation status of diverse protein substrates, bridging cellular metabolic state to post-translational regulation. Given their control over lactate production, several metabolic enzymes have been shown to influence histone lactylation, thereby regulating gene expression and disease progression. Here we highlight several representative examples. PFK promotes glycolysis and lactate production, which in turn enhances H3K18 lactylation. This epigenetic modification increases the transcriptional activity of zinc finger E-box-binding homeobox 1 ( ZEB1 ) and contactin 1 ( CNTN1 ), enhancing their protein levels and driving malignant phenotypes in tumor cells, including proliferation, migration, and invasion ( Wang R. et al., 2024 ; Shen et al., 2025 ). Similarly, enolase 2 (ENO2) and triosephosphate isomerase 1 (TPI1) promote glycolysis and lactate accumulation, leading to H3K18 lactylation, which induces epithelial-mesenchymal transition (EMT) and subsequently promotes the development of myopia ( Lin et al., 2024 ). LINC00183, a platelet-derived exosome component, binds to enolase 1 (ENO1) and enhances glycolysis, thereby driving H3K18 lactylation and promoting growth differentiation factor 15 (GDF15) expression. This axis ultimately supports the growth and metastasis of colorectal cancer ( Su et al., 2025 ). Isocitrate dehydrogenase 3β (IDH3β), a tricarboxylic acid (TCA) cycle enzyme, provides an additional layer of regulation. In Alzheimer’s disease (AD) and AD-transgenic mice’s brains, reduced IDH3β expression uncouples OXPHOS, thereby enhancing glycolysis and leading to lactate accumulation. This metabolic shift drives lactylation of histone sites including H4K12 and H4K8, which in turn enhances the expression of paired-box gene 6 (PAX6). PAX6 then inhibits IDH3β expression, forming a positive feedback IDH3β-lactate-histone lactylation-PAX6-IDH3β loop that ultimately accelerates AD deterioration ( Wang X. et al., 2024 ). In addition to regulating histone lactylation, glucose-metabolizing enzymes also promote lactylation of non-histone proteins, with broad functional implications. Chu et al. revealed that aldolase B (ALDOB) induces lactate production and activates pyruvate dehydrogenase kinase-1 (PDK1), thereby promoting lactylation of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6). This modification enhances CEACAM6 stability, leading to colon cancer cell proliferation and chemoresistance ( Chu et al., 2023 ). Elevated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein activity increases intracellular lactate concentration, which in turn promotes snail family transcriptional repressor 1 (SNAIL1) lactylation at K9, eventually resulting in fibroblast activation and pulmonary fibrosis ( Wu J. et al., 2025 ). PDHA1, when inactivated through acetylation, increases intracellular lactate concentration via inhibition of the TCA cycle. This mediates lactylation of the mitochondrial fission 1 protein (FIS1) at K20, further promoting excessive mitochondrial fission and leading to mitochondrial apoptosis, ultimately resulting in sepsis-associated acute kidney injury ( An et al., 2023 ). Phosphoenolpyruvate carboxykinase 1 (PCK1), a central gluconeogenic enzyme, binds to LDHA to promote lactylation of sterol regulatory element-binding protein (SREBP) regulating gene (SPRING) at K82. Enhanced mevalonate pathway activity resulting from this event inhibits ferroptosis and drives chemoresistance through the PCK1-LDHA-SPRINGlac axis ( Zhu et al., 2025b ).

Beyond direct lactylation of metabolic enzymes, lactylation modulates metabolism via two indirect routes: histone lactylation epigenetically regulates metabolic enzyme transcription, and lactylation of non-histone proteins affects metabolic enzyme expression or activity. Notably, these regulatory routes vary across different metabolic pathways, reflecting a diverse array of lactylation-mediated control mechanisms. Histone lactylation promotes glycolysis by epigenetically upregulating the transcription of key glycolytic enzymes. A recent study observed that enhanced H3K18la was enriched at the promoters of glucose metabolism genes and upregulated HK2 transcription, thereby driving liver macrophage M1 polarization and contributing to MASLD ( Li J. et al., 2025 ). Another study has shown that H4K79la and H4K91la enhance the transcription of LDHA , PGK1 , and HK1 , thereby forming a feedback loop that promotes breast cancer progression ( Liu J. et al., 2025 ). Histone lactylation has also been shown to promote the transcription of glycolytic enzyme genes, including PKM , leading to metabolic dysregulation and poor prognosis in non-small cell lung cancer ( Jiang et al., 2021 ). Furthermore, studies have found that H4K12la promotes PKM2 expression, thereby driving the progression of AD ( Pan et al., 2022 ). Beyond histone-mediated transcriptional regulation of metabolic enzymes, Wei et al. further reported that H3K18la promoted USP39 expression, and USP39 extended PGK1 half-life through its deubiquitinating activity, thereby enhancing glycolysis and accelerating tumor progression ( Wei et al., 2024 ). Non-histone proteins can also undergo lactylation to regulate metabolic enzymes involved in glucose metabolism. For instance, a study revealed that lactylation of discoidin, CUB, and LCCL domain-containing 1 (DCBLD1) at K172 increased its stability, which in turn promoted G6PD activation, ultimately accelerating cervical cancer progression ( Meng et al., 2024a ). Emerging evidence has established H3K18la as the most extensively characterized histone lactylation site in the regulation of lipid metabolism. In pancreatic cancer, a recent study showed that H3K18la promoted ACLY transcription, thereby promoting fatty acid synthesis and intracellular lipid accumulation, which subsequently drove cancer progression ( Lu et al., 2025 ). Similarly, another study has demonstrated that H3K18la promotes the transcription of elongation of very long chain fatty acids protein 5 ( ELOVL5 ), induces lipid peroxidation, and facilitates ferroptosis ( Hong J. et al., 2025 ). In liver cells, elevated H3K18la activated the CD36-NLRP3 inflammasome axis, promoting lipid accumulation and inflammation ( Li H. et al., 2025 ). In intervertebral disc degeneration and primary mouse pulmonary microvascular endothelial cells, lactate-driven H3K18la promoted ACSL4 transcription, thereby inducing ferroptosis ( Fang et al., 2025 ; Sun K. et al., 2025 ). In cervical cancer, H3K18la promoted GPD2 transcription, increased GPD2 expression, and consequently drove M2 macrophage polarization, contributing to malignant progression ( Huang C. et al., 2024 ). Beyond fatty acid metabolism, H3K18la also impacted cholesterol biosynthesis. A recent study reported that it promoted acetyl-CoA acetyltransferase 2 ( ACAT2 ) transcription and enhanced cholesterol secretion via small extracellular vesicles, thereby inducing M2 polarization of tumor-associated macrophages and establishing an immunosuppressive tumor microenvironment ( Yang Y. et al., 2025 ). H3K18la further drove steroid hormone production by promoting the transcription of cytochrome P450 family 11 subfamily A member 1 ( CYP11A1 ) ( Wu et al., 2024 ). H4K16la has also been implicated in metabolic regulation. One study revealed that it activated the transcription of pyruvate dehydrogenase kinase 4 ( PDK4 ). Subsequently, it formed a lactate-H4K16la-PDK4 feedback loop that drove metabolic reprogramming, promoting lactate and lipid accumulation, as well as liver damage ( Jiao et al., 2025 ). In addition to direct transcriptional regulation, lactylation of non-metabolic proteins can indirectly reshape lipid metabolism. Du et al. demonstrated that H3K18la promoted YTHDC1 expression, an m6A reader that stabilized m6A-modified nuclear enriched abundant transcript 1 (NEAT1). NEAT1 then recruited p300 to enhance histone acetylation at the stearoyl-CoA desaturase (SCD) promoter, thereby driving lipid metabolic reprogramming and hepatocellular carcinoma progression ( Du et al., 2024 ). A recent study showed that H3K14la promoted the PARK7-fatty acid desaturase 1/2 (FADS1/2) axis, through which FADS1/2 promoted long-chain polyunsaturated fatty acid (PUFA) metabolism, conferring resistance to ferroptosis and alleviating acute lung injury ( Xu J. et al., 2025 ). Non-histone lactylation has also been implicated in lipid metabolism. A recent study reported that apolipoprotein C-II (APOC2) underwent K70 lactylation, enhancing its interaction with lipoprotein lipase, thereby promoting free fatty acid release and immunotherapy resistance in non-small cell lung cancer ( Chen et al., 2024b ). In neuronal protection, lactylation of methyl-CpG binding protein 2 (MECP2) at K210 and K249 inhibited PLA2G6 transcription, an enzyme that hydrolyzes glycerophospholipids to release free fatty acids and lysophospholipids, thereby attenuating neuronal apoptosis and preventing ischemic brain injury ( Sun M. et al., 2025 ). Lactylation dynamics also impacted cholesterol metabolism. Zinc-finger MIZ-type-containing protein 1 (ZMIZ1) underwent K843 lactylation, which enhanced its binding to Nanog homeobox ( NANOG ), increasing NANOG transcriptional activity. NANOG subsequently promoted the expression of Niemann-Pick disease type C2 (NPC2), thereby enhancing cholesterol uptake, cancer stemness, and tamoxifen resistance in breast cancer ( Liu et al., 2025c ). Wang et al. demonstrated that HDAC2-dependent PD-L1 K189 delactylation promoted its nuclear localization and binding to the transcription factor YY1, thereby increasing SQLE transcription, promoting cholesterol biosynthesis, and facilitating liver cancer growth ( Wang X. et al., 2025 ). Histone lactylation has been shown to regulate amino acid metabolism by epigenetically modulating the transcription of key enzymes. A recent study by Huang et al. revealed that H3K18la modification enhances cysteine desulfurase ( NFS1 ) transcription. NFS1 upregulation promotes iron-sulfur (Fe-S) cluster biosynthesis, thereby reducing ferroptosis susceptibility and driving hepatocellular carcinoma metastasis following insufficient microwave ablation ( Huang et al., 2025 ). She and colleagues demonstrated that H3K18la promotes arginase 1 (ARG1) expression, leading to mitochondrial dysfunction and PANoptosis in ischemia/hypoxia-induced vascular dysfunction. Although ARG1 is a key enzyme in converting arginine to urea and ornithine, its role in the urea cycle was not addressed ( She et al., 2025 ). Lactylation of non-histone proteins also indirectly modulates amino acid metabolism. For instance, p300-mediated YY1 K183 lactylation was shown to promote IDO1 expression in tryptophan metabolism, thereby aggravating autoimmune uveitis ( Huang J. et al., 2024 ). Furthermore, Lu et al. identified that, in lenvatinib-resistant hepatocellular carcinoma models, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) K76 lactylation enhanced its binding to PCK2 and nuclear factor erythroid 2-related factor 2 ( NRF2 ) mRNAs, promoting their expression. This modification reprogrammed serine metabolism, and the resulting increase in S-adenosylmethionine drove m6A methylation of PCK2 and NRF2 mRNAs, forming a positive feedback loop that sustained their expression and lenvatinib resistance ( Lu et al., 2024 ). Compared with glucose and lipid metabolism, evidence for indirect regulation of nucleotide metabolism via lactylation remains limited. A recent study demonstrated that H3K18la promoted Ras homolog enriched in striatum ( RASD2 ) transcription. Subsequently, RASD2 enhanced the stability of the pyrimidine metabolic enzyme CTP synthase 1 (CTPS1) by promoting its SUMOylation and inhibiting its ubiquitination, thereby contributing to endometriosis progression ( Wang Z. et al., 2025 ).

Accumulating evidence has linked lactylation of metabolic enzymes to tumor progression across various cancer types ( Figure 6 ), with context-dependent outcomes ranging from enhanced proliferation to modulated drug resistance. Due to space limitations, this section focuses solely on the most prevalent cancer types worldwide. Information on lactylation of metabolic enzymes identified in other cancer types is provided in Section 3 and Figure 6 , and Table 1 . Metabolic enzyme lactylation and human diseases. Protein lactylation influences the onset and progression of various diseases, including cancer, inflammation, tissue injury and organ damage, degenerative diseases, metabolic dysfunction-associated fatty liver disease, and others. IVDD, intervertebral disc degeneration; CAVD, calcific aortic valve disease; DMI, diabetic myocardial infarction; SICD, sepsis-induced cardiac dysfunction; MIRI, myocardial ischemia-reperfusion injury; VI, vascular injury; BC, breast cancer; PaC, pancreatic cancer; OC, ovarian cancer; CC, cervical cancer; OI, osseous injury; GBM, glioblastoma; BI, brain injury; LUAD, lung adenocarcinoma; SI-ALI, sepsis-induced acute lung injury; RCC, renal cell carcinoma; CKD, chronic kidney disease; DKD, diabetic kidney disease; CRC, colorectal cancer; HCC, hepatocellular carcinoma; IRI, ischemia-reperfusion injury; NAFLD, non-alcoholic fatty liver disease; OA, osteoarthritis; RA, rheumatoid arthritis. Created with BioRender.com . In lung adenocarcinoma, lactylation of metabolic enzymes is associated with tumor aggressiveness, therapeutic resistance, and unfavorable clinical outcomes. Among these modifications, ENO1 and LDHA lactylation are involved in metabolic adaptation and resistance to osimertinib or cisplatin, respectively ( Gan et al., 2026 ; Li J. et al., 2026 ). G6PD lactylation is associated with enhanced malignant phenotypes, including increased proliferation and migration, whereas cGAS lactylation is linked to impaired immune function and poor prognosis, suggesting that lactylation may serve as an important regulator of lung adenocarcinoma progression ( Rao et al., 2025 ; Zhang Y. et al., 2025 ). In triple-negative breast cancer, LDHC4-mediated ACAA2 lactylation is associated with metabolic reprogramming and tumor progression, suggesting a potential contribution of metabolic enzyme lactylation to the development of triple-negative breast cancer ( Cui et al., 2025 ). In hepatocellular carcinoma, lactylation of metabolic enzymes has been associated with malignant progression, including enhanced cancer cell proliferation, stemness, and metastatic potential. ALDOA, PGAM1, and mitochondrial AK2 lactylation represent potential mechanisms linking metabolic enzyme regulation to hepatocellular carcinoma development and progression ( Yang Z. et al., 2023 ; Feng et al., 2024 ; Li Q. et al., 2026 ). In colorectal cancer, lactylation of metabolic enzymes has emerged as a potential regulator of tumor progression and therapeutic resistance. PKM2 and ME2 lactylation are associated with enhanced malignant phenotypes, including vascular mimicry, drug resistance, and tumor cell proliferation, whereas PFKP and ALDOA lactylation have been identified in colorectal cancer cells with their functional roles requiring further investigation ( Cheng et al., 2024 ; Li C. et al., 2025 ; Li W. et al., 2026 ). Collectively, these findings demonstrate that lactylation of metabolic enzymes regulates tumor progression across diverse cancer types, often in a context- and site-specific manner, providing potential targets for therapeutic intervention. Lactylation of metabolic enzymes also plays a role in modulating inflammatory responses, with effects that vary depending on the specific enzyme and cellular context ( Figure 6 ). In inflammatory diseases, lactylation of metabolic enzymes has emerged as an important regulator of disease progression by reshaping cellular metabolism and inflammatory responses. In macrophage-mediated inflammation, PKM2 lactylation contributes to metabolic reprogramming and promotes an anti-inflammatory phenotype ( Wang et al., 2022 ). In interstitial kidney inflammation, osteoarthritis, and rheumatoid arthritis, lactylation of metabolic enzymes such as CS, UGDH, ACLY, and GPI is associated with enhanced inflammatory responses, tissue damage, and disease progression, highlighting the potential role of metabolic enzyme lactylation in inflammatory disease regulation ( Zhang Y. et al., 2024 ; Lan et al., 2025 ; Tan et al., 2025 ; Yu et al., 2025 ). Lactylation of metabolic enzymes has emerged as a significant contributor to various cardiovascular pathologies, ranging from valve disease and endothelial dysfunction to myocardial injury ( Figure 6 ). In cardiovascular diseases, lactylation of metabolic enzymes has been implicated in disease progression through diverse pathological processes. In calcific aortic valve disease, GAPDH lactylation contributes to disease development, whereas ENO1 and HADHA lactylation are associated with endothelial dysfunction and cardiac metabolic impairment during sepsis ( Wang C. et al., 2025 ; Zhang T. N. et al., 2025 ; Xie et al., 2026 ). In diabetic myocardial infarction, IDH2 lactylation is linked to improved angiogenic responses and disease outcomes ( Zang et al., 2025 ). Furthermore, MDH2 and GPX4 lactylation contribute to myocardial ischemia-reperfusion injury by promoting mitochondrial dysfunction and ferroptosis, respectively, highlighting the involvement of metabolic enzyme lactylation in cardiovascular disease progression ( She et al., 2024 ; Wang Y. et al., 2025 ). Lactylation of metabolic enzymes has emerged as a potential regulator of tissue injury across multiple organs. In ischemic stroke, PLBD1 lactylation is associated with neuronal damage and neurological dysfunction ( Zhou F. et al., 2025 ). In bone infection, PGK1 lactylation contributes to mitochondrial impairment and ferroptotic damage, thereby promoting bone tissue destruction ( Qin et al., 2026 ). Moreover, LPCAT2 and PCK2 lactylation are involved in the progression of sepsis-induced lung injury and liver ischemia-reperfusion injury, respectively, through metabolic dysregulation and ferroptosis ( Yuan et al., 2025 ; Deng et al., 2026 ). These findings highlight the potential role of metabolic enzyme lactylation in tissue injury and organ dysfunction. In intervertebral disc degeneration, lactylation of metabolic enzymes has been implicated in disease progression through the regulation of oxidative stress and cell death pathways. In intervertebral disc degeneration, ACSL4-associated lactylation events contribute to nucleus pulposus cell dysfunction and tissue degeneration ( Sun K. et al., 2025 ). In diabetic nephropathy, ACSF2 lactylation is associated with mitochondrial dysfunction and oxidative damage under hyperglycemic conditions, highlighting the potential role of metabolic enzyme lactylation in chronic disease development ( Chen et al., 2024a ). In non-alcoholic fatty liver disease, MPC1-dependent regulation of FASN lactylation contributes to hepatic lipid homeostasis and disease progression. Reduced FASN lactylation favors lipid accumulation, whereas enhanced lactylation suppresses hepatic fat synthesis, suggesting that metabolic enzyme lactylation may represent an important link between metabolic remodeling and fatty liver disease development ( Gao et al., 2023 ). In PE, altered lactylation patterns in placental trophoblasts have been associated with impaired placental function and disease development. HK2 lactylation is involved in regulating trophoblast proliferation, and its disruption under oxidative stress may contribute to PE pathogenesis, highlighting the potential role of metabolic enzyme lactylation in pregnancy-related disorders ( Chen Z. et al., 2025 ).