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PubMed2025

Comprehensive profiling of lysine lactylation in Candida albicans and exploratory analysis of fluconazole tolerance associations.

UNLABELLED: Candida albicans is the primary pathogen of invasive candidiasis in most regions worldwide, but the therapy options for C. albicans infections are limited, and drug tolerance further exacerbates the treatment challenges. Lysine lactylation (Kla), a recently identified post-translational modification (PTM), is observed in numerous organisms; however, the role of Kla in C. albicans remains unknown. Hence, we report the first proteomic analysis of this specific modification in C. albicans and discuss its potential roles in drug tolerance of C. albicans. Altogether, 7,233 lactylation sites on 1,608 lactylated proteins were identified in C. albicans, with the highest degree of lactylation among the species studied so far. The further bioinformatics analysis revealed that the lactylated proteins were implicated in a variety of cellular functions with diverse subcellular localizations. Additionally, we found a unique survival mode of tolerant cells in the presence of fluconazole, which will be subject to a more thorough investigation in our future studies. This paper is the first report on the lactylome of Candida spp. and provides a reliable foundation for further research on Kla in C. albicans and other human pathogens. IMPORTANCE: This is the first report on the lactylome of Candida spp., and it provides some valuable insights for further research on lactylation in C. albicans and other human pathogens. Moreover, the observations in tolerant cells have prompted plausible hypotheses regarding the potential role of lactylation in mediating C. albicans tolerance to fluconazole, thereby offering a conceptual framework for subsequent investigations. Notably, fungal tolerance to azoles, a concept distinct from resistance, represents a critical phenomenon in C. albicans with profound clinical implications, as it directly correlates with therapeutic failure and persistent infections.

Candida albicans↗

PubMed2026

Both L-Lactyl and D-Lactyl Enantiomers Modify Histones in Mouse Testis.

Dynamic histone posttranslational modifications are crucial to precisely orchestrate gene expression programs. The recently discovered histone lysine lactylation has already been explored in various pathological contexts, but less in normal tissues. This modification exists as two enantiomers, L- and D-lactylation; the former may more likely modify histones due to abundant L-lactate produced by glycolysis. Here, we report the identification by proteomics of L- and D-lactylation on lysines of histones H3 and H4 in mouse testis. We developed a targeted proteomic analysis of histone peptides using synthetic sequences modified by L- or D-lactyl, to acquire reliable identification and quantification data. Some histone peptides bearing either enantiomer are separated by reversed-phase chromatography. Interestingly, despite the fact that L-lactate is much more abundant than D-lactate in mouse testis, we estimated abundance ratios of L-over D-lactylation to lie between 0.4 and 1.6 on seven residues of histones H3 and H4. Next, targeted proteomic analyses were performed on histones extracted from meiotic and postmeiotic male germ cells (spermatocytes and round spermatids, respectively), which are known to use L-lactate as a main source of energy. Nonetheless, residues 18 and 23 of histone H3 (H3K18 and H3K23) were reliably quantified and shown to harbor balanced amounts of both enantiomers. The stoichiometry of lactylation is low over the whole sequence of H3 and H4, representing about 0.01 to 0.44%: this contrasts with acetylation which exists at up to 25 to 35% relative abundances on some N-terminal lysines. Yet, lactylation appears to be more abundant than acetylation on the C-terminal half of H3 and H4, where the latter modification is scarce. Collectively, our results suggest a mechanism producing a mixture of the two enantiomers of lactate, or of a more direct substrate for lactylation, that leads to the modification of histones by L- and D-lactylation.

Animals↗

PubMed2026

Hyperlactate-Associated Lysine Lactylome Remodeling in Laryngeal Squamous Cell Carcinoma.

Laryngeal squamous cell carcinoma (LSCC) lacks reliable biomarkers, and the roles of lactate metabolism and lysine lactylation (Kla) remain largely unknown. We profiled the lysine lactylome of LSCC, paired it with adjacent normal tissues, and integrated the data with quantitative proteomic and transcriptomic analyses. LSCC exhibited a hyperlactate-associated phenotype characterized by dysregulated lactate-related genes (LRGs), altered protein abundance, increased tissue lactate, and globally increased Kla levels. Data-independent acquisition mass spectrometry (DIA-MS) identified 1616 Kla sites on 1468 peptides from 688 proteins, with most differential sites being upregulated in tumors. Differentially lactylated proteins were enriched in cell-matrix adhesion, cell migration, chromatin remodeling, and gene-regulatory processes and were clustered into cytoskeletal and nuclear regulatory modules. Multiple Kla sites were also detected on the core histones. Immunoblotting and tissue microarray analyses confirmed increased pan-Kla expression in the LSCC. Pan-Kla levels were independent of sex and age but positively correlated with the tumor stage and lymph-node metastasis. These findings provide a systematic resource for hyperlactate-associated lactylome remodeling in LSCCs and identify candidate Kla-related molecular features associated with clinicopathological progression for future functional and clinical evaluation.

Humans↗

PubMed2026

Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal adjacent tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in nonhistone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated 3-hydroxy-3-methylglutaryl reductase degradation 1 complex expression, may exert potential proapoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced poly(ADP-ribose) polymerase 1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.

Humans↗

PubMed2026

HDGF induces inflammatory cancer-associated fibroblast formation through ENO1-mediated glycolytic reprogramming in esophageal squamous-cell carcinoma.

Inflammatory cancer-associated fibroblasts (iCAFs) are a highly plastic stromal population that critically shape tumor progression, immunosuppression, and therapeutic response in esophageal squamous-cell carcinoma (ESCC). Epithelial-intrinsic programs are increasingly recognized as key determinants of fibroblast reprogramming within the tumor microenvironment, yet the underlying mechanisms remain incompletely understood. Here, we identified hepatoma-derived growth factor (HDGF) as a pivotal epithelial-intrinsic regulator that drives iCAF formation in ESCC. Mechanistically, nuclear HDGF functioned as a transcriptional activator by directly binding the ENO1 promoter, thereby upregulating the expression of the glycolytic enzyme enolase 1, enhancing aerobic glycolysis, and promoting lactate secretion from tumor cells. Tumor-derived lactate was subsequently taken up by CAFs and induced histone H4 lysine 12 lactylation (H4K12la), which epigenetically activated NF-κB signaling and promoted iCAF formation. Functionally, HDGF-induced iCAFs promoted tumor progression through activation of the IL-6/JAK1/STAT3 axis and established an immunosuppressive microenvironment characterized by increased recruitment of regulatory T cells and reduced infiltration of CD8+ T cells, thereby facilitating immune evasion. Therapeutically, blockade of ENO1 effectively disrupted the glycolysis-lactylation cascade, markedly suppressing tumor growth and iCAF formation in vivo. Moreover, ENO1 inhibition reprogrammed the immunosuppressive tumor microenvironment and significantly enhanced the efficacy of anti-PD-1 therapy. Collectively, our findings reveal an HDGF/ENO1/H4K12la/iCAF axis that links tumor metabolic reprogramming, stromal inflammatory activation, and immunosuppression in ESCC, identifying this axis as a promising therapeutic target for overcoming immunotherapy resistance.

Phosphopyruvate Hydratase↗

PubMed2026

LDHC4 promotes ovarian cancer progression through H4K12 lactylation to regulate PGK1 expression and modulate glycolysis.

OBJECTIVE: Ovarian cancer (OC) pathogenesis involves metabolic and epigenetic alterations, yet the underlying mechanisms remain unclear. Here, we sought to investigate the role and regulatory mechanism of lactate dehydrogenase C4 (LDHC4) in OC progression. METHODS: Multi-omics approaches were employed, including analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts, tissue microarrays, molecular biology experiments, and in vivo mouse models. LDHC4 expression was modulated in OC cell lines (A2780 and ES-2) to assess its effects on proliferation, migration, invasion, and metastasis. Lactylproteomic profiling, cleavage under targets and tagmentation (CUT&Tag), and chromatin analyses were conducted to explore epigenetic mechanisms. The functional role of the downstream glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was examined using pharmacological inhibition. Molecular docking and xenograft models were used to evaluate the therapeutic potential of targeting H4K12lac (lactylation of histone H4 at lysine 12). RESULTS: LDHC4 was significantly overexpressed in OC tissues and associated with poor overall survival (OS) (hazard ratio [HR] = 4.017, 95% confidence interval [CI]: 2.308–6.989, P < 0.0001). It promoted proliferation, migration, invasion, and metastasis in vitro and in vivo. LDHC4 overexpression increased global lactylation, notably upregulating H4K12lac, which was enriched at the PGK1 promoter. Inhibition of PGK1 with CBR-470-1 (half-maximal inhibitory concentration [IC₅₀] = 14.56 µM) suppressed OC growth and metastasis. Importantly, Elbasvir, identified as a high-affinity H4K12lac inhibitor, significantly reduced tumor burden in mouse xenografts across multiple doses (10–20 mg·kg⁻¹) and downregulated H4K12lac and Ki-67 expression. CONCLUSION: We conclude that LDHC4 promotes OC progression via lactylation-mediated epigenetic upregulation of PGK1. Targeting this pathway through H4K12lac inhibitors such as Elbasvir thus emerges as a viable therapeutic approach for OC.

Female↗

PubMed2026

Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.

Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4-MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.

Glioblastoma↗

PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗