Search Results (62)

Protein lysine lactylation is an emerging post-translational modification with broad roles in metabolic regulation. The yak (Bos grunniens) has evolved strong metabolic adaptability on the Qinghai–Tibetan Plateau, yet its tissue-specific lactylation patterns remain poorly characterized. Here, we collected liver, muscle, and heart tissues from three adult male yaks (4.5 years; 305–355 kg) and integrated quantitative proteomics with lactylomics to map lactylation profiles across these tissues. After normalizing each lactylation site to its parent protein abundance and applying Benjamini–Hochberg correction, we identified 628, 982, and 541 differentially lactylated sites (|log2FC| ≥ 0.585, adjusted p < 0.05) in liver–muscle, liver–heart, and muscle–heart comparisons, with median fold changes of 4.11, 7.08, and 3.08, corresponding to 267, 372, and 219 proteins, respectively. Subcellular localization showed that approximately 27–30% of these sites were localized to mitochondria. Functional enrichment across these comparisons consistently highlighted pathways such as the TCA cycle (fold enrichment: 1.56–2.38) and HIF-1 signaling (up to 2.69). A total of 135 proteins were common to all three comparisons, some with both up- and downregulated sites within the same tissue pair. Our results reveal decoupling between protein abundance and lactylation levels, tissue-specific lactylation patterns on the same proteins, and expression-independent lactylation of key enzymes (e.g., LDHA, SIRT3). Functional enrichment suggests lactylation serves as a multimodal regulatory mechanism coordinating energy metabolism, protein homeostasis, and electromechanical coupling across tissues. Expression profiling of lactate-metabolizing enzymes and lactylation regulators further supports an organ-specific model of post-translational regulation. Collectively, these findings detail a complex, tissue-specific lactylation network in yaks and provide insights into the metabolic homeostasis essential for high-altitude life. Full article

Histone deacetylase 3 (HDAC3) is a key node linking immunometabolism, chromatin regulation, and inflammatory transcriptional programs. Rather than functioning simply as a nuclear deacetylase, HDAC3 output is jointly shaped by corepressor-complex assembly, metabolic and acyl-substrate availability, and compartment-specific substrate access. The identification of lysine lactylation and the discovery of delactylase activity in HDAC1–3 have expanded the mechanistic boundaries of HDAC3, repositioning it from a canonical deacetylase toward an emerging regulatory node involved in the dynamic control of multiple acyl modifications. This review examines the complex-dependent activation of HDAC3, its regulation of nuclear inflammatory transcriptional thresholds, the proposed redistribution of its catalytic output across acetylated and lactylated substrates under increased lactate load, and candidate extra-nuclear non-histone acylation networks involving inflammatory signaling proteins and metabolic enzymes. Current evidence supports bona fide delactylase activity of HDAC3 in biochemical systems; however, whether HDAC3 directly delactylates specific cytoplasmic substrates in physiologically relevant settings requires further validation at the compartmental, site-specific, and functional levels. Viewing HDAC3 as an immunometabolic rheostat helps explain its context-dependent functions in inflammatory homeostasis, acute activation, and metabolic stress, and provides a conceptual basis for developing selective, complex-state-sensitive, and function-stratified HDAC3-targeted strategies. Full article

Background: Cardiac hypertrophy, a major feature of heart failure, is closely linked to metabolic remodeling and energy deficiency. Lysine lactylation (Kla), a recently discovered post-translational modification (PTM), has been implicated in various cellular processes. However, its specific role in cardiac hypertrophy remains poorly understood. Methods: We conducted quantitative proteomics and Kla PTM analysis on left ventricular tissues from both sham-operated and aortic banding-induced hypertrophic mouse hearts. Protein samples were extracted, enriched for lactylation, and subjected to mass spectrometry. Bioinformatic analyses were performed to uncover pathways and protein–protein interactions (PPI) related to Kla-modified proteins. Results: Our lactylome analysis identified 159 Kla-modified sites across 80 proteins, with 72 proteins exhibiting elevated Kla levels, particularly in mitochondrial and sarcomeric proteins. Pathway enrichment analysis highlighted significant involvement of fatty acid metabolism, the tricarboxylic acid (TCA) cycle, and cardiomyopathy-related pathways, underscoring the role of Kla in energy metabolism and cardiac remodeling. PPI analysis further revealed the central role of metabolic and structural proteins in the hypertrophic response. Conclusions: Our study provides the comprehensive analysis of Kla in cardiac hypertrophy, revealing its significant role in modulating proteins involved in mitochondrial energy metabolism and sarcomeric structure. Our findings provide a comprehensive overview of the lactylation landscape in cardiac hypertrophy and reveal extensive lactylation changes in proteins associated with mitochondrial metabolism and sarcomeric organization. These observations suggest a potential link between Kla and cardiac hypertrophy, which warrants further functional investigation. Full article

Lysine lactylation (Kla) is a recently discovered post-translational modification implicated in energy metabolism, cellular reprogramming, and disease progression. Here, we train the existing ProteinBERT-based predictor PBertKla on an integrated multi-source dataset and augment it with a lightweight machine-learning (ML) layer over sequence-derived features to predict Kla sites; on a common blind test set, the resulting model (PBertKla + ML) reaches an area under the receiver operating characteristic curve (AUROC) of 0.9126 on the integrated set and is statistically indistinguishable from the strongest available tool (Auto-Kla, DeLong p = 0.74) while significantly exceeding a recent ProtBert-based method (PCBert-Kla, p = 4 × 10⁻¹⁵). Two elements support this result. First, to train and benchmark the model, we assembled and released the largest curated Kla dataset to date, Multi (26,034 samples compiled from nine published sources through a 9-step quality-control pipeline), as a community resource. Second, we validated the model under a leakage-controlled protocol: re-training the complete pipeline under protein-level, 40%-identity homology, and leave-one-study-out splits—each verified to have zero train–test overlap—maintained ≈0.90 AUROC, only 0.6–1.5 percentage points (pp) below the random-split value, confirming genuine generalization rather than memorization. Ablation and SHapley Additive exPlanations (SHAP) analyses locate the predictive signal primarily in the ProteinBERT metafeature, with the ML layer adding a modest but real increment (+0.63 pp over PBertKla alone on Multi; no significant gain on the smaller hepatocellular carcinoma (HCC) set). Finally, an exploratory AlphaFold-based structural case study of FAM210A illustrates how predicted Kla sites distribute across ordered and disordered regions, without claiming a quantitative structure–probability relationship. All trained weights and code are publicly available. Full article

Lactate was traditionally considered a metabolic by-product of anaerobic glycolysis, mainly associated with tissue hypoxia and muscle fatigue. However, increasing evidence has redefined lactate as a multifunctional metabolic intermediate and signaling molecule involved in exercise-induced systemic adaptations. During physical activity, circulating lactate levels rise markedly when skeletal muscle production exceeds systemic clearance, allowing lactate to act as an exercise-responsive metabolite, or exerkine, and as a mediator of cardiometabolic adaptation. In the cardiovascular system, lactate serves not only as an efficient substrate for myocardial energy production but also as a regulator of vascular tone, endothelial function, angiogenesis, inflammation, and cardiac remodeling. These effects occur through receptor-dependent and receptor-independent mechanisms, including activation of hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), modulation of intracellular redox balance, and histone or non-histone protein lactylation. This review summarizes current evidence on lactate in cardiovascular physiology and disease, focusing on myocardial lactate metabolism, HCAR1/GPR81 signaling, protein lactylation, extracellular vesicle communication, gut microbiota interactions, and therapeutic implications in heart failure, atherosclerosis, and diabetic cardiomyopathy. Although lactate is also produced under resting, postprandial, and pathological conditions, exercise is characterized by the amplitude and kinetics of lactatemia, coordinated hormonal and hemodynamic responses, and transient high-concentration signaling. These features support exercise-derived lactate as a context-dependent cardiovascular exerkine. Full article

This review argues that protein lactylation—a lactate-driven posttranslational modification—serves as the long-sought molecular bridge that coordinates these two hallmarks in gastric cancer (GC). Far from being a passive metabolic byproduct, lactylation operates as a central molecular hub with a dual function: intracellularly, it directly drives malignant phenotypes by modifying key oncoproteins such as YAP and metabolic enzymes; extracellularly, it remodels the tumor immune microenvironment by polarizing tumor-associated macrophages toward an immunosuppressive M2 phenotype, upregulating PD-L1 expression, and impairing CD8⁺ T-cell function. We propose that these two arms constitute a self-reinforcing metabolic–epigenetic–immunological circuit, wherein lactylation both originates from and perpetuates the Warburg effect, creating a vicious cycle that sustains malignancy and immune evasion. This framework positions lactylation not merely as a mechanistic detail, but as a unifying principle that integrates metabolic reprogramming, epigenetic regulation, and immune suppression in GC. We critically evaluate the current landscape of lactylation “writers,” “erasers,” and “readers”; highlight the translational potential of targeting this pathway; and identify the conceptual and technical bottlenecks that must be overcome—including the lack of causality in current studies, the absence of specific research tools, and the unresolved heterogeneity of lactylation across cell types and disease stages. By reframing lactylation as an actionable hub rather than a downstream consequence, this review provides a roadmap for advancing lactylation-based precision medicine in GC. Full article

Platinum resistance remains a major obstacle in ovarian cancer, yet whether abnormal glycolysis and lactate metabolism drive this phenotype through protein lactylation remains unclear. Here, we investigated the role of lactate-driven protein lactylation in platinum resistance and sought to identify the key effector event involved. Global protein lactylation was assessed by immunohistochemistry in tumor samples from 122 patients with high-grade serous ovarian cancer, and integrated proteomic and lactylomic analyses were performed in fresh frozen tumors from 12 patients, followed by validation in ovarian cancer cell models and functional assays. Platinum resistant ovarian cancer exhibited enhanced glycolysis, increased lactate accumulation, and elevated global protein lactylation, which was associated with platinum resistance and shorter progression free survival. Integrated lactylome profiling identified ZMYM2 K529 lactylation as a platinum resistance associated event, and ZMYM2 was upregulated in platinum resistant tissues and cells. Mechanistically, lactate promoted ZMYM2 K529 lactylation, suppressed ubiquitin–proteasome mediated degradation, and increased ZMYM2 stability and abundance. Functionally, ZMYM2 enhanced cisplatin tolerance, homologous recombination repair, and tolerance to DNA damaging treatments. However, both wild-type ZMYM2 and the K529R mutant restored platinum-resistant phenotypes in ZMYM2-knockdown cells, indicating that K529 lactylation primarily maintains ZMYM2 stability rather than directly determining its downstream pro-resistance activity. Collectively, these findings identify a glycolysis–lactate–ZMYM2 lactylation axis that promotes platinum resistance in ovarian cancer and highlight lactylation-dependent ZMYM2 stabilization as a potential therapeutic vulnerability. Full article

High lactate concentration is a hallmark of the tumor microenvironment (TME). Regulatory T cells (Tregs) exhibit unique metabolic adaptability to this lactate-rich environment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that the monocarboxylate transporter MCT4 is upregulated in tumor-infiltrating Tregs and mediates direct lactate uptake. Using Treg-specific conditional knockout (cKO) mice, we show that MCT4 deficiency does not affect basal Treg development but abrogates lactate-induced Foxp3 stabilization and impairs Treg suppressive function. Mechanistically, MCT4-mediated lactate uptake promotes the lactylation of Foxp3 at lysine 277 (K277), which competitively inhibits its ubiquitination, thereby enhancing Foxp3 protein stability and nuclear localization. Nuclear Foxp3 subsequently interacts with IRF3 to promote IL-10 transcription and secretion. In the B16 melanoma model, MCT4-deficient Tregs display compromised stability and reduced tumor infiltration, leading to enhanced CD8⁺ T cell effector function and attenuated tumor growth. Collectively, our findings reveal that MCT4-mediated lactate uptake sustains Treg stability and function through Foxp3 lactylation, identifying MCT4 as a potential therapeutic target for modulating Treg activity in cancer. Full article

Breast cancer is prevalent and deadly, affecting women worldwide. Increasing research suggests that lysine lactylation (KLA) and DNA damage repair (DDR) play critical roles in tumor progression and that KLA and DDR are interconnected, as KLA can modulate DDR protein function, thereby influencing genome stability and drug response, while DDR signaling can reciprocally reshape lactate metabolism and KLA activity. In this study, we developed a novel prognostic gene signature (KLA and DDR index, KLDRI) based on KLA- and DDR-related genes. Model genes (PGK1, MORF4L2, RAD54B, RPA3, CCND2) were generated via LASSO-Cox regression. Patients were stratified into high- and low-risk groups according to KLDRI, the robust prognostic value of which was demonstrated via survival and validation analyses in the TCGA cohort and the METABRIC and GSE96058 cohorts, respectively. Tumor microenvironment analysis indicated an immunologically suppressed phenotype in high-risk patients, whereas low-risk patients exhibited an immune-inflamed microenvironment. Drug sensitivity analysis indicated reduced sensitivity to multiple chemotherapy and targeted therapy drugs in the high-risk group. Single-cell transcriptomic analysis revealed differential gene expression patterns between risk groups. A prognostic nomogram based on KLDRI was developed to predict overall survival. Furthermore, functional experiments demonstrated that RPA3 knockdown suppressed cancer cell proliferation and migration, sensitized cells to cisplatin treatment, and reduced global lactylation, which may serve as a novel biomarker and potential therapeutic target. These findings enhance our understanding of the interplay between KLA, DDR, and breast cancer progression, facilitating the development of personalized therapeutic strategies. Full article

Protein lactylation, an emerging post-translational modification (PTM) driven by the metabolite lactate, has surfaced as an important regulatory layer contributing to the crosstalk between metabolic reprogramming and cellular functional plasticity in colorectal cancer (CRC). Within the unique “host–microbiota” symbiotic microenvironment of CRC, the Warburg effect—fueled jointly by oncogene activation and microbial metabolism—provides abundant substrates for lactylation. This modification is dynamically regulated by a complex enzymatic system comprising “Writers” (e.g., p300/CREB-binding protein [p300/CBP], alanyl-tRNA synthetase 1/2 [AARS1/2]) and “Erasers” (e.g., histone deacetylases [HDACs] and Sirtuins). Through intricate crosstalk with other PTMs, such as acetylation and ubiquitination, lactylation exerts critical regulatory effects on both the histone epigenetic landscape and non-histone protein functions. Functionally, lactylation not only drives malignant proliferation, invasion, and metastasis but also systematically remodels the immunosuppressive “cold” tumor microenvironment. Furthermore, it confers broad-spectrum resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by orchestrating a ferroptosis defense network, enhancing DNA damage repair (DDR), and activating protective autophagy. This review systematically synthesizes the regulatory networks and biological functions of lactylation in CRC, deeply elucidating the core mechanisms underlying therapy resistance. Finally, we discuss the clinical translational potential of lactylation as a novel diagnostic/prognostic biomarker and therapeutic target, aiming to provide new theoretical foundations and strategic directions for overcoming current bottlenecks in CRC clinical treatment. Full article

Once written off as nothing more than a waste product of glycolysis, lactic acid is now seen as a key signaling molecule that operates across a wide range of physiological and pathological processes, from immune regulation and tumor metabolism to neural function. But its role goes beyond energy metabolism and cell signaling. Recent studies have uncovered a new type of post-translational modification called histone lactylation, in which lactate itself provides the lactoyl group attached to lysine residues on histones. This modification directly ties a cell’s metabolic state to the epigenetic control of gene expression. For example, histone lactylation helps shift macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype by fine-tuning gene transcription. In this review, we walk through the discovery and biochemical foundation of histone lactylation; discuss the likely writer and eraser enzymes that manage its dynamic changes; and highlight recent advances in understanding the role of this modification in inflammation, tumorigenesis, neurological disorders, and interactions with gut microbes. We also lay out key unanswered questions and consider why targeting protein lactylation might open up new therapeutic possibilities. Full article

Sirtuin 1 (SIRT1) is an important protein for maintaining cellular homeostasis, and targeting SIRT1 represents a promising strategy for alleviating osteoporosis. The discovery of highly potent and safe SIRT1 activators therefore holds significant translational value for clinical anti-osteoporosis therapies. In this study, we performed deep mining of high-throughput RNA-sequencing (RNA-seq) data from 576 young and aged skeletal stem/progenitor cells (SSPCs) and identified SIRT1 downregulation as a critical hallmark of SSPC ferroptosis during aging-related osteoporosis. In SIRT1 heterozygous deficiency (SIRT1^+/−) mice, we found that SIRT1 deficiency triggered SSPC ferroptosis and induced premature osteoporosis. Computer-aided drug design (CADD) was employed to screen 9634 compounds targeting the SIRT1 active site, leading to the identification of the natural compound Hydroxygenkwanin (HGK) as a novel SIRT1 activator. HGK treatment effectively restored SIRT1 activity, suppressed ferroptosis in SSPCs in vitro, and ameliorated osteoporosis in vivo. Through transcriptomic analysis and lactylation profiling, we further found that HGK can activate SIRT1 and reverse the lactylation-mediated suppression of the enzymatic activities of SOD1 and PRDX1. This mechanism may underlie the ability of HGK to reduce SSPC ferroptosis and alleviate osteoporosis. Overall, our findings suggest that HGK possesses translational potential for the treatment of osteoporosis through SIRT1 activation. Full article

Background/Objectives: Immune evasion remains a critical barrier to effective hepatocellular carcinoma (HCC) therapy. Lactate dehydrogenase A (LDHA) drives lactate accumulation and histone lysine lactylation (Kla), reshaping the immunosuppressive microenvironment, while bromodomain-containing protein 4 (BRD4) sustains B7-H3 transcription via super-enhancer occupancy. Despite their synergistic roles in the lactate–Kla–B7-H3 immunosuppressive axis, no dual-target inhibitor simultaneously engaging both proteins has been reported. This study aimed to discover dual LDHA/BRD4 inhibitors from natural product libraries using an integrated AI-driven computational pipeline. Methods: We established a multi-tier virtual screening cascade comprising Lipinski/QED drug-likeness filtration, DiffDock-based AI docking, QuickVina binding energy validation, PLIP interaction profiling, 200 ns all-atom molecular dynamics simulations, MM-GBSA binding free energy calculations, and density functional theory analysis. Natural product libraries from COCONUT and CMNPD databases (84,730 compounds post-filtration) were screened against both targets. Results: High-throughput DiffDock screening identified 11 dual-target hits, from which CNP0038114.1 and CMNPD16582 emerged as prioritized lead candidates. All four protein–ligand complexes maintained structural stability throughout MD simulations, with MM-GBSA binding free energies ranging from −27.24 to −32.45 kcal/mol, predominantly driven by van der Waals interactions. DFT calculations revealed distinct electronic profiles: CNP0038114.1 exhibited a narrow HOMO–LUMO gap (2.718 eV) favoring charge-transfer reactivity, whereas CMNPD16582 displayed a larger gap (4.822 eV), suggesting superior chemical stability. Conclusions: This computational study furnishes two novel natural product leads for targeting the lactate–Kla–B7-H3 immunosuppressive axis in HCC, establishing a generalizable AI-driven workflow for dual-target inhibitor discovery. Full article

Vitiligo is characterized by epidermal melanocyte destruction, with autoreactive CD8⁺ T cells playing a central pathogenic role, yet the mechanisms driving their hyperactivation remain unclear. Lactate has emerged as a key immunometabolite that functions as both a signaling molecule and an epigenetic modulator via protein lactylation. Nevertheless, the role of lactate in vitiligo pathogenesis has not been explored. Here, we report that serum lactate levels are significantly elevated in vitiligo patients and correlate positively with disease activity. In a mouse model, lactate administration accelerated vitiligo progression, accompanied by increased CD8⁺ T cell infiltration and melanocyte destruction in lesional skin. In vitro, lactate enhanced CD8⁺ T cell effector molecule expression (granzyme B, perforin, IFN-γ, CD107a) and cytotoxic function. Mechanistically, lactate increased global protein lactylation in CD8⁺ T cells, with marked enrichment at histone H3 lysine 9 (H3K9). H3K9 lactylation (H3K9la) was associated with enhanced chromatin accessibility and transcriptional activation of effector genes, as revealed by RNA sequencing and CUT&Tag analyses. Pharmacological inhibition of lactate production or lactylation abrogated these effects. Collectively, our findings identify lactate as a critical driver of CD8⁺ T cell pathogenicity in vitiligo through H3K9la-mediated epigenetic reprogramming, highlighting lactate metabolism and lactylation as potential therapeutic targets. Full article

Vibrio alginolyticus is a common pathogenic bacterium and can cause diseases in aquaculture animals. Lysine lactylation (Kla) is a novel post-translational modification (PTM) that has been confirmed to play critical roles in key biological processes. However, the modification landscape and functions of Kla in V. alginolyticus remain unclear. In this study, lactylation modification profiles of the bacterial pathogen V. alginolyticus were first systematically characterized; a total of 9308 lactylation sites on 2155 proteins were successfully identified. The lactylation of cAMP receptor protein (CRP) and triosephosphate isomerase (TPI) was verified by Co-immunoprecipitation (Co-IP) and Western blot to validate the lactylome data. Bioinformatic analysis of the Kla sites revealed 32 conserved sequence motifs surrounding the modified residues. Kla proteins were mainly involved in central metabolic pathways, including glycolysis/gluconeogenesis and ribosome biogen regulators were found to contain Kla modification sites. To investigate crosstalk among lysine acylations in V. alginolyticus, we integrated Kla, lysine acetylation (Kac), and lysine succinylation (Ksuc) profiles and identified 337 co-modified proteins and 5 co-modified sites. Additionally, phylogenetic analysis of Vibrio alginolyticus CobQ based on protein sequence alignment revealed no homology to the known delactylase CobB. Combined in vitro and in vivo functional validation identified VaCobQ as a candidate delactylase with potential NAD⁺-independent activity. This study establishes a lysine lactylation landscape in V. alginolyticus, providing a resource for exploring Kla functions in bacterial metabolism and its possible connections to virulence. Full article