This article systematically reviews the biochemical properties, metabolic regulation mechanisms, and roles of histone lysine L-lactylation (KL-la) in transcriptional regulation, with a focus on distinguishing it from its isomers, elucidating its biosynthetic pathways, and mapping its enzymatic regulatory network, thereby deepening our understanding of the crosstalk between metabolism and epigenetic regulation.
Literature Overview
The article 'Biochemistry and Regulation of Histone Lysine L-Lactylation,' published in Nature Reviews Molecular Cell Biology, reviews and summarizes the chemical properties, metabolic origins, regulatory enzyme systems, and functional roles of histone lysine L-lactylation (KL-la)—a novel histone modification—in gene expression and cellular physiology. The article systematically outlines the discovery of KL-la, strategies for distinguishing isomers, and the functions of writers, erasers, and readers, while deeply exploring the nuclear synthesis mechanism of L-lactyl-CoA and two independent lactylation pathways, emphasizing its pivotal role in linking cellular metabolism to epigenetic regulation. The entire section is coherent and logical, ending with a Chinese period.Background Knowledge
Histone lysine lactylation is a short-chain acyl modification driven by the metabolic byproduct L-lactate, first discovered in 2019 and rapidly emerging as a hotspot in the intersection of epigenetics and metabolism. This modification is similar to classical acetylation but introduces a bulkier lactyl group with a hydroxyl moiety, endowing it with unique spatial conformation and hydrogen-bonding capacity, potentially mediating distinct chromatin conformations and functional outcomes. Current studies have confirmed that KL-la plays regulatory roles in macrophage polarization, tumor progression, neuronal activity, and DNA repair, and is closely associated with hypoxia, glycolysis, and the Warburg effect. However, KL-la has three isomers: L-lactylation (KL-la), D-lactylation (KD-la), and N-ε-(carboxyethyl)-lysine (Kce), which have identical mass but different structures, leading to functional divergence. Among them, KL-la is enzymatic, reversible, and site-specific, whereas KD-la and Kce are primarily non-enzymatic byproducts derived from side reactions of methylglyoxal and D-lactoylglutathione. Therefore, accurate discrimination among these isomers is crucial for studying their biological significance. Moreover, the synthesis and spatial distribution of L-lactyl-CoA are key determinants of KL-la specificity; the discovery of nuclear synthetases GTPSCS and ACSS2 reveals a novel regulatory mode where metabolic enzymes directly supply energy within the nucleus. Although multiple lactylation substrates have been identified, the global functions, dynamic regulatory mechanisms, and disease-related potential of KL-la remain to be systematically elucidated. This article systematically reviews the biochemical basis and regulatory network of KL-la, providing a theoretical framework for subsequent mechanistic studies and disease interventions.
Research Methods and Experiments
The study employed high-resolution mass spectrometry, specific antibody enrichment, single amino acid derivative analysis (e.g., Mosher’s acid method), and biochemical enzyme activity assays to systematically identify and distinguish the three isomers—KL-la, KD-la, and Kce. By developing specific antibodies targeting different isomers (e.g., pan-KL-la, pan-KD-la) and combining them with ChIP-seq and proteomics technologies, the research team clarified the non-random distribution of KL-la on chromatin and its association with transcriptionally active regions. Additionally, using gene knockout, point mutation, and protein interaction analyses, the functions of GTPSCS and ACSS2 as nuclear L-lactyl-CoA synthetases were revealed, along with their complex formation mechanisms with histone lactyltransferases such as p300/CBP and KAT2A. Furthermore, isotope labeling experiments (e.g., ^13C-glucose and ^13C-lactate) traced the metabolic flux from L-lactate to L-lactyl-CoA and KL-la, confirming its metabolic dependence. For the L-lactyl-CoA-independent pathway mediated by AARS1/2, in vitro lactylation assays, Km determination, and mutant functional analyses revealed its dual-substrate characteristics and physiological roles under specific conditions.Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically elucidates the biochemical basis and regulatory mechanisms of KL-la, establishing its central role as a metabolic sensor and providing a new perspective on how cells convert metabolic states into epigenetic instructions. The discovery of KL-la expands the chemical diversity of histone modifications, revealing that lactate is not merely a metabolic byproduct but also an important signaling molecule. Future research should further define the dynamic landscape of KL-la under various physiological and pathological conditions and explore its roles in development, immunity, and neural function. Moreover, small-molecule intervention strategies targeting KL-la regulatory enzymes (e.g., GTPSCS, AARS1/2) or reader proteins may offer novel therapeutic avenues for cancer, inflammation, and metabolic diseases. Simultaneously, developing more sensitive detection tools and site-specific antibodies will facilitate deeper mechanistic insights into KL-la.
Conclusion
This article comprehensively summarizes the biochemical properties, metabolic origins, and regulatory networks of histone lysine L-lactylation (KL-la), emphasizing its critical role as a bridge connecting cellular metabolism to epigenetic regulation. The study establishes that KL-la is the predominant form of lactylation, enzymatically generated from L-lactate via L-lactyl-CoA-dependent reactions, with its nuclear synthesis driven by GTPSCS and ACSS2, forming complexes with lactyltransferases such as p300 to ensure modification specificity and efficiency. In contrast, D-lactylation and Kce are non-enzymatic byproducts with minimal abundance and limited functionality. Additionally, the non-canonical pathway mediated by AARS1/2 exists but contributes minimally to histone modification. The dynamic regulation of KL-la involves specific writers, erasers, and readers, enabling precise transcriptional control. Despite potentially low stoichiometry, local enrichment of KL-la is sufficient to exert significant biological functions. This research not only deepens our understanding of the diversity of histone modifications but also provides a theoretical foundation and potential targets for disease interventions targeting the metabolism-epigenetics axis. Future studies should focus on functional validation of KL-la in various disease models and explore its potential as a biomarker or therapeutic target.
