The discovery of lactylation as a post-translational modification has fundamentally transformed our understanding of lactate's role in cellular biology. While initially recognized for its effects on histone modifications, emerging research reveals that non-histone lactylation represents an equally significant regulatory mechanism with profound implications for disease pathogenesis and therapeutic intervention.
Expanding Beyond Histone Modifications
Non-histone lactylation affects a vast array of cellular proteins, with proteomic studies identifying 273 lysine lactylation sites within 166 proteins in various biological systems. Unlike histone lactylation, which primarily influences chromatin structure through modifications of H3 and H4, non-histone lactylation impacts diverse cellular components including metabolic enzymes, transcription factors, and signal transduction molecules.
The modification occurs through the enzymatic transfer of lactyl groups from lactyl-CoA to lysine residues on target proteins. This process is mediated by several "writer" enzymes, including the acetyltransferase P300, lysine acetyltransferase 8 (KAT8), and notably, alanyl-tRNA synthetases AARS1 and AARS2, which represent a novel class of lactylation enzymes distinct from traditional acetyltransferases.
Metabolic Integration and Disease Pathogenesis
The metabolic basis of lactylation links cellular energy production directly to protein function regulation. Under conditions of enhanced glycolysis, such as the Warburg effect in cancer cells, increased lactate production drives widespread lactylation modifications. This metabolic-epigenetic coupling allows cells to rapidly adjust protein function in response to changing energy demands.
In cardiovascular diseases, lactylation demonstrates both protective and pathological roles. The lactylation of α-myosin heavy chain at K1897 promotes interaction with titin and reduces heart failure risk, while lactate-induced endothelial-to-mesenchymal transition contributes to cardiac fibrosis following myocardial infarction. Exercise-induced lactylation of methyl-CpG-binding protein 2 (MeCP2) promotes M2 macrophage polarization and enhances plaque stability in atherosclerotic cardiovascular disease.
Neurological and Immune System Implications
Non-histone lactylation significantly impacts neurological function and immune responses. In brain diseases, lactylation affects microglial activation and neuroinflammatory responses. Under hypoxic conditions, p53 lactylation in microglia promotes proinflammatory phenotypes, while lactylation of transcription factor YY1 regulates angiogenesis in retinal diseases.
The modification also plays crucial roles in immune regulation. In sepsis, lactate uptake by macrophages leads to HMGB1 lactylation through p300/CBP-dependent mechanisms, disrupting endothelial integrity and promoting disease progression. Conversely, lactylation can promote anti-inflammatory responses, as demonstrated by exercise-induced SNAP91 lactylation that prevents anxiety-like behaviors.
Cancer Biology and Therapeutic Implications
In oncology, non-histone lactylation emerges as a critical driver of tumor progression through multiple mechanisms. The modification affects key oncogenes and tumor suppressors, with AARS1-mediated p53 lactylation at K120 and K139 sites compromising its tumor suppressor function. Similarly, lactylation of cyclin E2 (CCNE2) promotes hepatocellular carcinoma cell proliferation.
DNA damage repair represents another crucial area where lactylation influences cancer biology. Lactylation of MRE11 at K673 and NBS1 at K388 enhances homologous recombination repair, contributing to chemotherapy resistance. The modification of XRCC1 at K247 promotes nuclear translocation and DNA repair activity, further supporting tumor cell survival under therapeutic stress.
The tumor microenvironment is significantly shaped by lactylation-mediated immune suppression. Lactate-induced MOESIN lactylation at K72 enhances regulatory T cell stability and function, while lactylation of RIG-I inhibits inflammasome activation, both contributing to immune evasion.
Dynamic Regulation and Therapeutic Targeting
The reversible nature of lactylation, mediated by "eraser" enzymes including HDACs and sirtuins, provides opportunities for therapeutic intervention. HDAC1-3 and SIRT1-3 demonstrate delactylation activity, with HDAC3 showing particular efficacy against both L- and D-lactate modifications.
Therapeutic strategies targeting lactylation pathways show promising results. Small molecule inhibitors like D34-919 specifically block protein interactions involved in lactylation-mediated drug resistance. β-alanine treatment can inhibit p53 lactylation and restore tumor suppressor activity. Cell-penetrating peptides targeting specific lactylation sites demonstrate potential for overcoming chemotherapy resistance.
Clinical Translation and Future Directions
The clinical relevance of non-histone lactylation extends beyond basic research, with lactylation-related gene signatures serving as prognostic biomarkers across multiple cancer types. Risk models based on lactylation-related genes effectively predict patient outcomes and treatment responses in gastric cancer, hepatocellular carcinoma, and other malignancies.
Current therapeutic approaches focus on modulating lactate production through lactate dehydrogenase inhibitors, blocking lactate transport via monocarboxylate transporter inhibitors, and directly targeting lactylation enzymes. The combination of these approaches with existing therapies, particularly immunotherapy, shows synergistic effects in preclinical models.
Challenges and Opportunities
Despite significant progress, several challenges remain in translating lactylation research to clinical applications. The tissue-specific and context-dependent nature of lactylation effects requires careful consideration in therapeutic design. Additionally, the potential for off-target effects when modulating such a fundamental cellular process necessitates precise targeting strategies.
Future research directions include identifying additional lactylation writers and erasers, characterizing tissue-specific lactylation patterns, and developing more selective inhibitors. The integration of lactylation modulation with existing therapeutic modalities, particularly in combination with immunotherapy and targeted cancer treatments, represents a promising avenue for improving patient outcomes.
The emergence of non-histone lactylation as a critical regulatory mechanism highlights the complex interplay between metabolism and cellular function. As our understanding of this modification continues to evolve, it promises to unlock new therapeutic opportunities across a broad spectrum of diseases, from cancer to cardiovascular and neurological disorders.
