In recent years, the understanding of cellular metabolism has undergone a paradigmatic shift, with the metabolite L-lactate moving firmly from its status as a simplistic waste byproduct to an essential signaling molecule that orchestrates diverse biological functions. The groundbreaking discovery of protein L-lactylation, a novel post-translational modification driven by L-lactate, has fundamentally transformed our comprehension of how metabolic intermediates can dynamically influence cellular regulation. This emerging modification not only provides a direct link between cellular metabolic state and gene expression regulation but also reveals new dimensions of how cells adapt to physiological and pathological stimuli.
Protein lactylation, first characterized through histone modifications, constitutes the covalent attachment of lactate moieties to lysine residues on target proteins. This biochemical event extends beyond mere histone regulation, encompassing a variety of non-histone substrates and thereby broadening the scope of lactate’s influence within the cell. Unlike traditional epigenetic modifications such as acetylation and methylation, lactylation is intimately tied to metabolic flux, creating a molecular dialogue between metabolic activity and the control of gene transcription. This crosstalk underscores the sophistication with which cells integrate their metabolic environment with signaling pathways to direct fate decisions and functional outcomes.
The enzymology behind protein lactylation remains a critical focus area, with investigations identifying key enzymes responsible for installing and removing lactyl groups. Writers of this modification appear to utilize activated lactate derivatives, such as lactyl-CoA, as donors for the modification. Although the precise enzymatic players remain partially elusive, the paradigm suggests parallels with other acyltransferases, with a growing appreciation for the specialized machinery that couples metabolic products to epigenetic regulation. Meanwhile, dedicated "eraser" enzymes capable of removing lactyl marks are beginning to emerge, hinting at the dynamic and reversible nature of this modification that aligns it with classic epigenetic marks.
Functionally, histone lactylation has been implicated in the regulation of gene expression programs critical for cell differentiation, development, and responses to environmental challenges. For example, during macrophage activation, shifts in intracellular lactate levels modulate histone lactylation patterns, which in turn influence the transcriptional landscape governing inflammatory responses. This newly characterized dimension of metabolic-epigenetic interplay offers an explanation for how metabolic rewiring underlies cellular phenotypic plasticity and functional adaptation, effectively linking energy metabolism to immune function.
Beyond the nucleus, the identification of lactylation on non-histone proteins opens vast new frontiers for research. Lactylation can modulate the activity, localization, stability, and interaction networks of metabolic enzymes, signaling proteins, and transcription factors. These findings suggest a multifaceted regulatory framework where lactate signaling extends to numerous cellular compartments, shaping processes ranging from energy metabolism to signal transduction cascades. The breadth of this phenomenon implies that lactylation could serve as a universal mediator that fine-tunes cellular physiology in response to metabolic cues.
The pathophysiological implications of protein lactylation are profound. Elevated lactate levels and aberrant lactylation have been observed in diverse disease contexts, including cancer, cardiovascular disorders, and autoimmune diseases. Tumor cells, for instance, often exhibit heightened glycolysis and lactate production, which may fuel lactylation-dependent epigenetic reprogramming to promote malignancy, chemoresistance, and immune evasion. Understanding how lactylation pathways are hijacked in disease states presents opportunities to develop novel therapeutic interventions targeting these enzymatic processes or the downstream signaling effected by lactylated proteins.
In cardiovascular biology, accumulating data indicate that protein lactylation influences vascular remodeling, inflammation, and cardiac metabolism. The dynamic regulation of lactylation in response to ischemic stress and metabolic perturbations may underlie adaptive or maladaptive cardiac responses. Therapeutically modulating lactylation could therefore provide avenues to mitigate heart disease progression by restoring metabolic and gene expression homeostasis.
The developmental biology arena also stands to benefit from this burgeoning field, as evidence mounts for lactylation’s role in directing stem cell fate and tissue differentiation. Fluctuations in lactate levels during embryonic development may serve as metabolic signals that guide epigenetic modifications, thus shaping the complex choreography of gene expression necessary for proper organogenesis and morphogenesis.
Elucidating the crosstalk between lactylation and other post-translational modifications is an ongoing challenge. Proteins often undergo combinatorial modifications that collectively regulate their function, and understanding how lactylation fits into this regulatory code will be essential. Synergistic or antagonistic interactions with acetylation, methylation, phosphorylation, and ubiquitination may fine-tune cellular responses and contribute to the spatiotemporal precision of signaling networks.
Technological advances have been instrumental in unveiling the landscape of protein lactylation. Mass spectrometry-based proteomics, coupled with novel chemical probes and antibodies specific for lactylated residues, have enabled comprehensive identification and quantitation of lactylation sites. These tools continue to expand the catalog of lactylated proteins and provide mechanistic insights into their functional consequences across various biological systems.
The dynamics of lactate metabolism itself inform the regulation of lactylation. Cellular conditions that promote glycolytic flux, such as hypoxia or inflammatory stimuli, increase intracellular lactate pools, thereby enhancing the availability of lactyl donors. Conversely, metabolic reprogramming in response to nutrient deprivation or mitochondrial dysfunction can attenuate lactylation, linking environmental inputs with epigenomic landscapes. This metabolic sensitivity underscores the adaptability of lactylation as a cellular signaling modality.
From a therapeutic standpoint, targeting the enzymes responsible for lactylation presents an attractive strategy. Small molecules that inhibit "writers" or activate "erasers" of lactyl groups could modulate gene expression patterns and cellular phenotypes with precision. Additionally, understanding the interplay between lactylation and immune checkpoints may pave the way for innovative immunotherapies, especially in cancer and autoimmune conditions where metabolic dysregulation is prevalent.
Moreover, protein lactylation exemplifies the growing recognition that metabolites are not merely substrates or energy sources but also informational molecules that participate actively in cellular regulation. This realization opens new vistas in the field of metabolomics and epigenetics, bridging gaps between disciplines that historically operated in parallel. The metabolic-epigenetic interface embodied by lactylation exemplifies the multifunctional nature of small molecules in orchestrating biological complexity.
In conclusion, the discovery of protein L-lactylation as a metabolite-driven post-translational modification marks a pivotal advance in cell biology, revealing how metabolic signals are intimately wired to the control of gene expression and protein function. Its roles in physiology and disease extend from the nucleus to the cytoplasm, influencing development, immunity, cancer progression, and cardiovascular health. As research in this domain accelerates, unraveling the full spectrum of lactylation’s molecular mechanisms holds promise for novel diagnostic and therapeutic breakthroughs, transforming our approach to metabolic and epigenetic diseases alike.
Subject of Research: Protein L-lactylation as a post-translational modification regulating metabolic and signaling pathways in physiology and disease.
Article Title: The emerging role of protein L-lactylation in metabolic regulation and cell signalling.
Article References:
Ren, H., Tang, Y. & Zhang, D. The emerging role of protein l-lactylation in metabolic regulation and cell signalling.
Nat Metab 7, 647–664 (2025). https://doi.org/10.1038/s42255-025-01259-0
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