Lactate and lactylation in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Language: Английский

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Lactylation in health and disease: physiological or pathological?

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1787 - 1821

Published: Jan. 2, 2025

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles different aspects of energy metabolism signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as novel posttranslational modification (PTM). Research indicates that Kla essential balancing mechanism variety organisms involved many biological processes pathways. closely related to disease development represents potential important new drug target. In line with existing reports, we searched for newly discovered sites on histone nonhistone proteins; reviewed the mechanisms (particularly focusing enzymes directly reversible regulation Kla, including "writers" (modifying enzymes), "readers" (modification-binding "erasers" (demodifying enzymes); summarized crosstalk between PTMs help researchers better understand widespread distribution diverse functions. Furthermore, considering "double-edged sword" role both pathological contexts, this review highlights "beneficial" states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) "detrimental" pathogenic or inducive effects processes, particularly malignant tumors complex nontumor diseases. We also clarify molecular health disease, discuss feasibility therapeutic Finally, describe detection technologies their applications diagnosis clinical settings, aiming provide insights treatment diseases accelerate translation from laboratory research practice.

Language: Английский

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Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 10, 2025

Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely terminal product but also nexus for initiating physiological pathological responses body. Lysine lactylation (Kla), novel post-translational modification (PTM) proteins, has emerged pivotal mechanism by which exerts regulatory influence. This epigenetic potential alter gene expression patterns, thereby impacting Increasing evidence indicates correlation between adverse prognosis various malignancies. Consequently, this review article aims encapsulate proteins interact with lactate, elucidate tumorigenesis progression, explore therapeutic targets afforded modulation lactylation. The objective is clarify oncogenic provide strategic framework future directions burgeoning field.

Language: Английский

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Bioinformatics Identification of Lactate-Associated Genes in Hepatocellular Carcinoma: G6PD’s Role in Immune Modulation

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Background Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate-associated genes in HCC and their potential as therapeutic targets. Methods We analyzed RNA-seq clinical data from 374 patients The Cancer Genome Atlas (TCGA) database. Using Cox regression, LASSO analysis, Kaplan-Meier survival curves, we identified key patient outcomes. Functional validations, including Western blot, flow cytometry, molecular docking studies, were performed to confirm biological impact these genes. Results G6PD, IK, CALML5 significant markers for HCC. A model was developed that effectively stratified into risk groups, which correlated survival. G6PD’s role immune modulation its drug target validated through biochemical assays computational analyses. HepG2 cells confirmed alterations G6PD expression affect T cell activity, knockdown enhancing IFN-γ production overexpression inhibiting it, demonstrating evasion. Conclusions establishes metabolism genes, particularly validation immunomodulatory effects further supports strategies aimed at surveillance treatment outcomes

Language: Английский

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Establishment of a Lactylation‐Related Gene Signature for Hepatocellular Carcinoma Applying Bulk and Single‐Cell RNA Sequencing Analysis

International Journal of Genomics, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Background: Lactylation is closely involved in cancer progression, but its role hepatocellular carcinoma (HCC) unclear. The present work set out to develop a lactylation-related gene (LRG) signature for HCC. Methods: lactylation score of tumor and normal groups was calculated using the variation analysis (GSVA) package. single-cell RNA sequencing (scRNA-seq) HCC performed "Seurat" Prognostic LRGs were selected by performing univariate least absolute shrinkage selection operator (LASSO) Cox regression analyses validate Riskscore model. Functional enrichment conducted (GSEA) "clusterProfiler" Genomic characteristics between different risk compared, mutational burden (TMB) "Maftools" Immune cell infiltration assessed algorithms cell-type identification estimating relative subsets transcript (CIBERSORT), microenvironment populations-counter (MCP-counter), proportions immune cells (EPIC), estimation resource (TIMER), single-sample (ssGSEA). Immunotherapy response predicted dysfunction exclusion (TIDE) algorithm. Drug sensitivity analyzed "pRRophetic" A nomogram established "rms" expressions prognostic verified vitro test, counting kit-8 (CCK-8), wound healing, transwell assays carried measure viability, migration, invasion cells. Results: score, which higher group than group, has been confirmed as an independent factor evaluation Six LRGs, including two protective genes (FTCD APCS) four (LGALS3, C1orf43, TALDO1, CCT5), identified model with strong prediction performance scRNA-seq revealed that LGALS3 largely expressed myeloid cells, while APCS, FTCD, CCT5, C1orf43 mainly hepatocytes. high-risk primarily enriched pathways occurrence development, T infiltration. Moreover, found be less responsive immunotherapy more sensitive chemotherapeutic drugs. By integrating clinical features, high predictive accuracy developed. Additionally, highly Silencing CCT5 inhibited Conclusion: developed novel LRG could considered promising therapeutic target biomarker

Language: Английский

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Unveiling lactylation modification: A new hope for cancer treatment

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 184, P. 117934 - 117934

Published: Feb. 21, 2025

Language: Английский

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Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: March 8, 2025

Cancer remains the leading cause of mortality worldwide, and emergence drug resistance has made identification new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct glycolysis with limited ATP-producing capacity, recently gained recognition critical signaling molecule. It plays key role not only in cancer cell metabolism but also shaping tumor microenvironment (TME). Histone lysine lactylation, newly identified post-translational modification, been shown to influence range cellular processes cancer. Current research focuses on mechanisms functions histone lactylation cancer, including its gene expression regulation, signal transduction, protein synthesis. However, despite these advancements, there are still plenty barriers quest unravel modification. The single-cell spatial transcriptomics may offer valuable insights for selecting targets. This review provides comprehensive summary applications modification clinical settings. Through detailed analysis, we identify challenges limitations that exist current landscape. These lay groundwork future studies by highlighting promising directions.

Language: Английский

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A novel lactylation-related signature predicts the prognosis and is associated with immune infiltration in thyroid cancer

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Background​: Epigenetic regulator lactate, a glycolysis product, affects gene expression via histone lactylation, promoting tumor growth and immunosuppression. But its related genes' role in thyroid carcinoma (THCA) remains unclear.​ Methods​: Lactylation - genes from TCGA were consensus clustered. DEGs between clusters analyzed Cox regression, Random_forest, LASSO to create Lactylation High/Low risk signature. data was split for validation. Immune cell infiltration, GSEA, TIDE score drug sensitivity of the subtypes examined. A lactylation scoring model built as per prior method, lactate levels "Two risk" cluster" compared. Signature detected THCA GSE33630 datasets. Results​: Ten formed 2 prognostic valuable (p = 0.01) THCA. 137 identified these clusters. 7 signature (High Low risk) showed significant survival correlation < 0.001). infiltration GSEA analysis higher immune activity low group. The Exclusion suggested escape high nomogram including established prediction. Cluster B High group had poor prognoses. linked score, indicating more escape. Validation samples CLDN2, ARSI, SPOCD1, TUBB3 ATP2C2 expression. In conclusions​, the can not only serve marker (THCA), but may also provide new therapeutic targets it. Future studies should further validate potential this clinical application.

Language: Английский

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Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation

Cancer Medicine, Journal Year: 2025, Volume and Issue: 14(6)

Published: March 1, 2025

ABSTRACT Background Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate‐associated genes in HCC and their potential as therapeutic targets. Methods We analyzed RNA‐seq clinical data from 374 patients The Cancer Genome Atlas (TCGA) database. Using Cox regression, LASSO analysis, Kaplan–Meier survival curves, we identified key patient outcomes. Functional validations, including Western blot, flow cytometry, molecular docking studies, were performed to confirm biological impact these genes. Results G6PD, IK, CALML5 significant markers for HCC. A model was developed that effectively stratified into risk groups, which correlated survival. G6PD's role immune modulation its drug target validated through biochemical assays computational analyses. HepG2 cells confirmed alterations G6PD expression affect T cell activity, knockdown enhancing IFN‐γ production overexpression inhibiting it, demonstrating evasion. Conclusions establishes metabolism genes, particularly validation immunomodulatory effects further supports strategies aimed at surveillance treatment outcomes

Language: Английский

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Establishing a Prognostic Model Correlates to Inflammatory Response Pathways for Prostate Cancer via Multiomic Analysis of Lactylation‐Related Genes

International Journal of Genomics, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Prostate cancer (PCa) continues to pose substantial clinical challenges, with molecular heterogeneity significantly impacting therapeutic decision‐making and disease trajectories. Emerging evidence implicates protein lactylation—a novel epigenetic regulatory mechanism—in oncogenic processes, though its prognostic relevance in PCa remains underexplored. Through integrative bioinformatics interrogation of lactylation‐associated signatures, we established correlations using multivariable feature selection methodologies. Initial screening via differential expression analysis (limma package) coupled Cox proportional hazards modeling revealed 11 survival‐favorable regulators 16 hazard‐associated elements linked biochemical recurrence. To enhance predictive precision, ensemble machine learning frameworks were implemented, culminating a 10‐gene lactylation signature demonstrating robust discriminative capacity (concordance index = 0.738) across both primary (TCGA‐PRAD) external validation cohorts (DKFZ). Multivariable regression confirmed the score’s independence, exhibiting prominent associations clinicopathological parameters including tumor staging metastatic potential. The developed clinical‐molecular nomogram achieved superior accuracy (C − > 0.7) through synergistic integration biological covariates. Tumor microenvironment deconvolution uncovered distinct immunological landscapes, high‐risk stratification correlating enriched stromal infiltration immunosuppressive phenotypes. Pathway enrichment analyses implicated chromatin remodeling processes cytokine‐mediated inflammatory cascades as potential mechanistic drivers divergence. Therapeutic vulnerability profiling demonstrated response patterns: low‐risk patients exhibited enhanced immune checkpoint inhibitor responsiveness, whereas subgroups showed selective chemosensitivity docetaxel mitoxantrone. Functional PC‐3 models AK5 silencing induced proapoptotic effects, suppressed migration invasion, modulated regulation CD276 coexpression. These multimodal findings position dynamics, particularly AK5‐mediated pathways, promising targets biomarkers management.

Language: Английский

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