- Protein lactylation is a relatively recent post-translational modification (PTM) that has attracted considerable attention in molecular biology and biomedical research. It refers to the addition of a lactyl group to specific amino acid residues on proteins, particularly lysine residues, resulting in a modification known as lysine lactylation (Kla). Protein lactylation provides an important connection between cellular metabolism and protein regulation because changes in cellular lactate levels can influence the modification of proteins and, consequently, their activity, localization, stability, and biological functions.
- The discovery of histone lactylation provided the foundation for much of the current understanding of protein lactylation. Histones are proteins around which DNA is organized, and their chemical modifications can influence gene expression and chromatin structure. Histone lactylation demonstrated that lactate, traditionally regarded primarily as a product of glucose metabolism, can also participate in cellular signaling and gene regulation. This discovery helped establish the concept that metabolic changes can be directly translated into epigenetic signals.
- Lactate metabolism is therefore closely connected to protein lactylation. Lactate is produced during glycolysis, particularly when cells rely heavily on glycolytic metabolism. Although lactate was historically viewed mainly as a metabolic end product, research has shown that it can have broader signaling functions. Changes in intracellular lactate availability may influence the generation of lactylation-related metabolites and thereby affect the extent and distribution of protein lactylation.
- The glycolysis–lactate–lactylation axis represents an important link between cellular metabolism and gene regulation. When glycolytic activity increases, lactate production can rise, potentially altering lactylation levels on histones and other proteins. This creates a mechanism through which the metabolic state of a cell can influence transcriptional programs and cellular behavior. Such metabolic-epigenetic communication is particularly relevant in rapidly proliferating cells, activated immune cells, tumors, and tissues experiencing metabolic or environmental stress.
- Although histone lactylation initially received considerable attention, lactylation is not restricted to histones. Non-histone protein lactylation has increasingly been identified in different cellular compartments and on proteins involved in metabolism, signaling, cytoskeletal organization, transcription, and other biological processes. Modification of these proteins suggests that lactylation may regulate cellular functions through mechanisms extending far beyond chromatin and transcription.
- The molecular mechanisms responsible for protein lactylation are an active area of research. Lactyl groups can potentially be transferred to lysine residues through different biochemical mechanisms, and the cellular sources of the lactyl donor are being investigated. The precise enzymatic machinery responsible for adding lactyl groups to particular proteins, often described as lactyltransferases or writers, is not yet as comprehensively defined as the enzyme systems responsible for some better-established post-translational modifications. This remains an important question in the field.
- An equally important area is the identification of enzymes that remove lactyl groups. These potential delactylases or erasers could provide cells with a mechanism for reversing lactylation and dynamically controlling its effects. Histone deacetylases and other enzymes have been investigated for possible roles in regulating lactylation, but the specificity and biological importance of individual enzymes remain subjects of ongoing research. Understanding the balance between lactylation and delactylation will be essential for explaining how this modification is controlled.
- Another important consideration is the site specificity of lactylation. Different proteins may contain multiple lysine residues that can potentially undergo lactylation, and modification at different sites may produce different functional consequences. The identification of lactylation sites has been greatly assisted by mass spectrometry-based proteomics, which allows researchers to detect modified peptides and investigate the distribution of lactylated proteins across cells and tissues.
- Histone lactylation is particularly important because it provides a potential mechanism through which metabolic changes can influence transcription. Lactylation of histones may alter chromatin properties or affect the recruitment of proteins involved in gene regulation. Research has linked histone lactylation with changes in the expression of genes involved in inflammation, cell differentiation, metabolism, tissue repair, and other processes. The exact relationship between individual histone lactylation sites and transcriptional outcomes continues to be investigated.
- Protein lactylation has attracted significant interest in immunology and inflammation. Activated immune cells can undergo substantial metabolic changes, including changes in glycolysis and lactate production. Lactylation may therefore participate in communication between cellular metabolism and immune-cell function. Studies have suggested connections between lactylation and macrophage polarization, inflammatory responses, immune regulation, and tissue repair, although the precise mechanisms can vary according to cell type and physiological context.
- The relationship between macrophage metabolism and lactylation is one of the most studied areas of lactylation biology. Macrophages can undergo metabolic and functional changes in response to their environment, and lactate accumulation may influence their gene-expression programs through lactylation. This has led to interest in lactylation as a possible mechanism connecting metabolic conditions with macrophage phenotype and inflammatory behavior.
- Lactylation may also participate in cancer biology. Tumor cells frequently exhibit altered glucose metabolism and increased glycolytic activity, which can contribute to elevated lactate production in the tumor microenvironment. Increased lactate availability may influence protein lactylation and potentially affect gene expression, tumor-cell behavior, immune responses, angiogenesis, metabolism, and interactions between cancer cells and surrounding cells. Consequently, the lactate–lactylation pathway in cancer has emerged as an important research area.
- The tumor microenvironment provides a particularly interesting setting for studying lactylation. Cancer cells, immune cells, stromal cells, and other components of tumors interact within a metabolically complex environment. Lactate produced by one cell population can influence neighboring cells, potentially creating metabolic signals that affect their behavior. Lactylation may therefore represent one mechanism through which metabolic communication within tumors contributes to disease progression and immune regulation.
- Protein lactylation has also been investigated in hypoxia and cellular stress. Oxygen limitation can alter cellular metabolism and increase reliance on glycolysis, potentially changing intracellular lactate concentrations. Because lactylation can respond to metabolic conditions, it may form part of the cellular response to hypoxia, nutrient availability, oxidative stress, and other environmental challenges.
- Another emerging area is the relationship between lactylation and cell differentiation and development. Changes in metabolism accompany many differentiation processes, and lactylation may provide a molecular mechanism through which metabolic states influence transcriptional and functional changes. Research is investigating possible roles for lactylation in stem cells, immune-cell differentiation, tissue regeneration, and developmental processes.
- Lactylation may also interact with other epigenetic modifications, including acetylation, methylation, phosphorylation, ubiquitination, and other PTMs. These modifications can occur on the same proteins or within related regulatory pathways. Such epigenetic and post-translational modification crosstalk may determine how a cell interprets metabolic information and converts it into changes in protein function or gene expression.
- The study of lactylation has been greatly advanced by proteomics and epiproteomics. Modern mass spectrometry techniques can identify large numbers of lactylated proteins and potential lactylation sites simultaneously. Combining these approaches with transcriptomics, metabolomics, chromatin analysis, and biochemical experiments can help researchers determine whether a detected lactylation event is functionally important or simply reflects changes in cellular metabolism.
- An important challenge is distinguishing correlation from causation in lactylation research. An increase in cellular lactate and an increase in protein lactylation may occur simultaneously, but this does not necessarily mean that lactate directly causes every observed biological effect. Researchers therefore need to establish the enzymes involved, identify specific modification sites, determine how those modifications affect protein behavior, and demonstrate their physiological relevance.
- Protein lactylation is also being investigated in relation to cellular metabolism and metabolic diseases. Because lactate production and utilization are altered in conditions involving metabolic dysfunction, lactylation could potentially participate in adaptive or pathological cellular responses. However, the biological significance of lactylation in different metabolic diseases remains an active area of research.
- The potential importance of lactylation extends to therapeutic research. If specific lactylation enzymes, lactate-producing pathways, or lactylation-dependent signaling mechanisms are shown to contribute to disease, they could potentially become targets for therapeutic intervention. However, because lactylation is involved in normal cellular regulation as well as disease processes, manipulating this pathway will require a detailed understanding of its context-dependent functions.
- Overall, protein lactylation represents an emerging connection between metabolism, epigenetics, and cellular signaling. It expands the traditional view of lactate from a metabolic product to a molecule that can participate in broader regulatory networks. Through histone and non-histone protein modification, lactylation may influence gene expression, protein function, immune responses, metabolism, inflammation, tissue repair, and disease progression.
- The field is still developing, and many fundamental questions remain. Future research will need to clarify the complete lactylation machinery, including writers, erasers, readers, lactyl-group donors, substrate specificity, and regulatory mechanisms. It will also be important to determine how different lactylation sites affect individual proteins and how lactylation interacts with other post-translational and epigenetic modifications.
