Metformin Attenuates Neutrophil Recruitment through the H3K18 Lactylation/Reactive Oxygen Species Pathway in Zebrafish DOI Creative Commons
Ren Zhou,

Rui-Chen Ding,

Yu Qian

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(2), P. 176 - 176

Published: Jan. 30, 2024

Beyond its well-established role in diabetes management, metformin has gained attention as a promising therapeutic for inflammation-related diseases, largely due to antioxidant capabilities. However, the mechanistic underpinnings of this effect remain elusive. Using vivo zebrafish models inflammation, we explored impact on neutrophil recruitment and underlying mechanisms involved. Our data indicate that reduces histone (H3K18) lactylation, leading decreased production reactive oxygen species (ROS) muted response both caudal fin injury otic vesicle inflammation. To investigate precise through which modulates migration via ROS H3K18 meticulously established correlation between metformin-induced suppression lactylation levels. Through supplementary experiments involving restoration lactate ROS, our findings demonstrated elevated levels significantly promoted inflammatory zebrafish. Collectively, study illuminates previously unexplored avenues metformin's anti-inflammatory actions downregulation production, highlighting crucial epigenetic regulation inflammation pointing potential treating inflammation-associated conditions.

Language: Английский

Histone lactylation-driven B7-H3 expression promotes tumor immune evasion DOI Creative Commons
Zhibo Ma,

Jianming Yang,

Wenlong Jia

et al.

Theranostics, Journal Year: 2025, Volume and Issue: 15(6), P. 2338 - 2359

Published: Jan. 13, 2025

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous checkpoints, particularly those within B7 family. Elucidating mechanisms that govern induction family molecules is crucial for advancement immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, suggested may play role in reshaping tumor microenvironment and facilitating evasion. Methods: We analyzed glycolysis pathway's enrichment patients with immune-evading tumors assessed impact lactate treatment on antitumor immunity CD8+ T microenvironment. interrupted using dehydrogenase A (LDHA) knockdown sodium oxamate, evaluated its effects cell cytotoxicity. Additionally, we investigated correlation between B7-H3 expression pathway, explored molecular underlying lactate-induced expression. Results: Our findings revealed pathway was highly enriched tumors. Lactate inhibited cells, whereas interruption via LDHA or oxamate augmented cytotoxicity effectively counteracting found be closely linked pathway. Mechanistically, lactate-upregulated H3K18la directly bound promoter conjunction transcription factor Creb1 co-activator Ep300, leading increased contributing progression by compromising proportion tumor-infiltrating cells. In mouse bearing models, inhibiting suppressed growth, activated demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced efficacy anti-PD-1 treatment. Conclusions: This study uncovers novel mechanism which modulates through expression, providing new avenues metabolism-targeted

Language: Английский

Citations

3
Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment DOI Creative Commons

Shiming Tan,

Yiqing Yang, Wenjuan Yang

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: March 10, 2023

Metabolic reprogramming is one of the hallmarks cancer. As nutrients are scarce in tumor microenvironment (TME), cells adopt multiple metabolic adaptations to meet their growth requirements. not only present cells, but exosomal cargos mediates intercellular communication between and non-tumor TME, inducing remodeling create an outpost microvascular enrichment immune escape. Here, we highlight composition characteristics meanwhile summarize components corresponding sorting mode. Functionally, these cargos-mediated improves "soil" for metastasis. Moreover, discuss abnormal metabolism targeted by its potential antitumor therapy. In conclusion, this review updates current role TME enriches future application scenarios exosomes.

Language: Английский

Citations

41
Histone lactylation regulates cancer progression by reshaping the tumor microenvironment DOI Creative Commons
Junxing Qu, Peizhi Li, Zhiheng Sun

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 27, 2023

As a major product of glycolysis and vital signaling molecule, many studies have reported the key role lactate in tumor progression cell fate determination. Lactylation is newly discovered post-translational modification induced by lactate. On one hand, lactylation introduced new era metabolism microenvironment (TME), on other it provided breakthrough point for elucidation interaction between metabolic reprogramming epigenetic modification. Studies shown that cells, stem cells tumor-infiltrating immune TME can participate development cancer through downstream transcriptional regulation, potential promising treatment target. This review summarized discovery effects lactylation, as well recent research histone regulating reshaping TME. We also focused strategies to enhance anti-tumor via targeting lactylation. Finally, we discussed limitations existing proposed perspectives future order further explore targets. It may provide way direction improve prognosis.

Language: Английский

Citations

28
A review of lactate-lactylation in malignancy: its potential in immunotherapy DOI Creative Commons

Jinhui Zha,

Juanjin Zhang,

Jingfen Lu

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 8, 2024

Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate been widely observed in histone non-histone proteins, these play crucial role regulating gene expression by covalently attaching lactoyl groups lysine residues proteins. This discovery has greatly enhanced our comprehension lactic acid's involvement disease pathogenesis. In this article, we provide comprehensive review intricate relationship between immunity, occurrence lactylation malignant tumors, exploitation targeted lactate-lactylation immunotherapy. Additionally, discuss future research directions, aiming offer novel insights that could inform investigation, diagnosis, treatment related diseases.

Language: Английский

Citations

17
Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma DOI
Bo Hao,

Huixing Dong,

Rui Xiong

et al.

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 171, P. 108183 - 108183

Published: Feb. 22, 2024

Language: Английский

Citations

15
Lactylproteome analysis indicates histone H4K12 lactylation as a novel biomarker in triple-negative breast cancer DOI Creative Commons
Zhaolei Cui, Yanhong Li, Yingying Lin

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: May 8, 2024

Objective The established link between posttranslational modifications of histone and non-histone lysine (K) residues in cell metabolism, their role cancer progression, is well-documented. However, the lactylation expression signature triple-negative breast (TNBC) remains underexplored. Methods We conducted a comprehensive lactylproteome profiling eight pairs TNBC samples matched adjacent tissues. This was achieved through 4-Dimensional label-free quantitative proteomics combined with analysis (4D-LFQP-LA). identified lactylated proteins detected using immunoblotting immunohistochemistry (IHC) specific primary antibodies, clinicopathological prognostic significance evaluated. Results Our 58 sites on 48 proteins, delineating protein alteration TNBC. Bioinformatic functional analyses indicated that these play crucial roles regulating key biological processes Notably, at position 12 (H4K12lac) H4 domain found to be upregulated Further investigations showed high prevalence H4K12lac upregulation TNBC, positive rates 93.19% (137/147) 92.93% (92/99) tissue chip validation cohorts, respectively. correlated positively Ki-67 inversely overall survival (OS) (HR [hazard ratio] =2.813, 95%CI [credibility interval]: 1.242-6.371, P =0.0164), suggesting its potential as an independent marker (HR=3.477, 95%CI: 1.324-9.130, =0.011). Conclusions Lactylation significant post-translational modification proteins. emerges promising biomarker for offering insights into profiles linking clinical implications

Language: Английский

Citations

13
Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation DOI Creative Commons
Shuai Wang, Tengfei Huang, Qiulian Wu

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(22)

Published: Nov. 14, 2024

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show lactate production patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic histone lactylation, activating modification leads immunosuppressive transcriptional programs suppression of phagocytosis via upregulation CD47, "don't eat me" signal, in cells. Leveraging these findings, pharmacologic targeting augments efficacy anti-CD47 therapy. Mechanistically, lactylated interacts the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, binds acetyltransferase (HAT) EP300 induce increased substrate specificity lactyl-CoA shift cytokine profile. Targeting inhibits growth both cell–intrinsic phagocytosis. Collectively, results suggest mediates metabolism-induced contributes CD47-dependent immune evasion, which can be leveraged augment immuno-oncology therapies.

Language: Английский

Citations

13
Constructing lactylation-related genes prognostic model to effectively predict the disease-free survival and treatment responsiveness in prostate cancer based on machine learning DOI Creative Commons

Jinyou Pan,

Jianpeng Zhang, Jingwei Lin

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: March 19, 2024

Background: Prostate cancer (PCa) is one of the most common malignancies in men with a poor prognosis. It therefore great clinical importance to find reliable prognostic indicators for PCa. Many studies have revealed pivotal role protein lactylation tumor development and progression. This research aims analyze effect lactylation-related genes on PCa Methods: By downloading mRNA-Seq data TCGA PCa, we obtained differential related Five machine learning algorithms were used screen key then five overlapping construct survival model by lasso cox regression analysis. Furthermore, relationships between pathways, mutation immune cell subpopulations, drug sensitivity explored. Moreover, two risk groups established according score calculated (LRGs). Subsequently, nomogram scoring system was predict disease-free (DFS) patients combining clinicopathological features scores. In addition, mRNA expression levels verified lines qPCR. Results: We identified 5 LRGs (ALDOA, DDX39A, H2AX, KIF2C, RACGAP1) constructed model. The AUC values 1 -, 3 5-year DFS dataset 0.762, 0.745, 0.709, respectively. found better predictor than traditional A that combined variables accurately predicted outcome patients. high-risk group higher proportion regulatory T cells M2 macrophage, burden, worse prognosis those low-risk group. had lower IC50 certain chemotherapeutic drugs, such as Docetaxel, Paclitaxel be highly expressed castration-resistant cells. Conclusion: can effectively therapeutic responses

Language: Английский

Citations

12
Unlocking the multifaceted molecular functions and diverse disease implications of lactylation DOI
Fengyang Jing, Jianyun Zhang, Heyu Zhang

et al.

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

ABSTRACT In recent years, a significant breakthrough has emerged in biology, the identification of lactylation, novel post‐translational process. This intriguing modification is not limited to specific class proteins but occurs across diverse range, including histones, signalling molecules, enzymes, and substrates. It can exert broad regulatory role various diseases, ranging from developmental anomalies neurodegenerative disorders inflammation cancer. Thus, it presents exciting opportunities for exploring innovative treatment approaches. As result, there been surge research interest, leading deeper understanding molecular mechanisms functions underlying lactylation within physiological pathological processes. Here, we review detection biological disease effects, providing systematic overview this modification.

Language: Английский

Citations

12
Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy DOI
Xuan Ni,

Chengpiao Lu,

Guo-qiang Xu

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: 45(8), P. 1533 - 1555

Published: April 15, 2024

Language: Английский

Citations

11