Regulation of macrophage activation by lactylation in lung disease DOI Creative Commons
Yungeng Wei, Hua Guo,

Shixing Chen

et al.

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

Published: July 4, 2024

Lactylation is a process where lactate, cellular metabolism byproduct, added to proteins, altering their functions. In the realm of macrophage activation, lactylation impacts inflammatory response and immune regulation. Understanding effects on activation vital in lung diseases, as abnormal function are pivotal conditions like pneumonia, pulmonary fibrosis, COPD, cancer. This review explores concept lactylation, its regulation recent research progress diseases. It offers new insights into disease pathogenesis potential therapeutic targets.

Language: Английский

The role of lactate in cardiovascular diseases DOI Creative Commons
Jun Ouyang, Hui Wang, Jiangnan Huang

et al.

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 3, 2023

Abstract Cardiovascular diseases pose a major threat worldwide. Common cardiovascular include acute myocardial infarction (AMI), heart failure, atrial fibrillation (AF) and atherosclerosis. Glycolysis process often has changed during these diseases. Lactate, the end-product of glycolysis, been overlooked in past but gradually identified to play biological functions recent years. Similarly, role lactate disease is being recognized. Targeting production, regulating transport, modulating circulating levels may serve as potential strategies for treatment future. The purpose this review integrate relevant clinical basic research on pathophysiological years clarify important guide further studies exploring other

Language: Английский

Citations

54
Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma DOI Creative Commons
Fei Li, Wenzhe Si,

Li Xia

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 6, 2024

Abstract Background Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type mark, which links glycolysis metabolite process lactylation. However, role lactylation in PDAC remains unclear. Methods The level was identified by western blot immunohistochemistry, its relationship with overall survival evaluated using Kaplan-Meier plot. participation growth progression confirmed through inhibition inhibitors or lactate dehydrogenase A ( LDHA ) knockdown both vitro vivo. potential writers erasers were functional experiments. target genes H3K18 (H3K18la) screened CUT&Tag RNA-seq analyses. candidate TTK protein kinase BUB1 mitotic checkpoint serine/threonine B BUB1B validated ChIP-qPCR, RT-qPCR Next, effects these two overexpression. interaction between Co-IP assay. Results Histone lactylation, especially H3K18la elevated PDAC, high associated poor prognosis. suppression glycolytic activity different kinds contributed anti-tumor E1A binding p300 (P300) deacetylase 2 writer eraser cells, respectively. enriched at promoters activated transcription regulators . Interestingly, could elevate expression P300 turn increased glycolysis. Moreover, phosphorylated tyrosine 239 (Y239) LDHA, subsequently upregulated levels. Conclusions glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction PDAC. These findings delivered exploration significant inter-relationship metabolic regulation, might pave way toward novel treatment strategies therapy.

Language: Английский

Citations

49
Ubiquitous protein lactylation in health and diseases DOI Creative Commons
Junyong Wang, Ziyi Wang,

Q Wang

et al.

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: Feb. 5, 2024

Abstract For decades, lactate has been considered a byproduct of glycolysis. The shuttle hypothesis shifted the paradigm, demonstrating that not only plays important roles in cellular metabolism but also communications, which can transcend compartment barriers and occur within among different cells, tissues organs. Recently, discovery induce novel post-translational modification, named lysine lactylation (Kla), brings forth new avenue to study nonmetabolic functions for lactate, inspired ‘gold rush’ academic commercial interest. Zhang et al. first showed Kla is manifested histones as epigenetic marks, then mounting evidences demonstrated occurs diverse non-histone proteins. widespread faithfully orchestrates numerous biological processes, such transcription, inflammatory responses. Notably, dysregulation touches myriad pathological processes. In this review, we comprehensively reviewed curated existing literature retrieve identified sites on both proteins summarized recent major advances toward its regulatory mechanism. We thoroughly investigated function underlying signaling pathway summarize how regulates various processes normal physiological states. addition, further highlight effects development human diseases including inflammation response, tumorigenesis, cardiovascular nervous system other complex diseases, might potentially contribute deeply understanding interpreting mechanism pathogenicity. Graphical

Language: Английский

Citations

35
Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma DOI Creative Commons

LI Guan-zhang,

Di Wang, You Zhai

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(8), P. 1696 - 1710.e10

Published: Aug. 1, 2024

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for development of new treatments. Here, we that interaction between ALDH1A3 and PKM2 enhances latter's tetramerization promotes lactate accumulation stem cells (GSCs). By scanning lactylated proteome lactate-accumulating GSCs, XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated shows a stronger affinity importin α, allowing greater nuclear transposition enhanced DNA repair. Through high-throughput screening small-molecule library, D34-919 potently disrupts ALDH1A3-PKM2 interaction, preventing ALDH1A3-mediated enhancement tetramerization. In vitro vivo treatment chemoradiotherapy-induced apoptosis GBM cells. Together, our findings potential therapeutic target to improve response chemoradiotherapy ALDH1A3hi GBM.

Language: Английский

Citations

34
Lactylome Analysis Unveils Lactylation‐Dependent Mechanisms of Stemness Remodeling in the Liver Cancer Stem Cells DOI Creative Commons
Fan Feng,

Jiaqin Wu,

Qingjia Chi

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(38)

Published: Aug. 5, 2024

Lactate plays a critical role as an energy substrate, metabolite, and signaling molecule in hepatocellular carcinoma (HCC). Intracellular lactate-derived protein lysine lactylation (Kla) is identified contributor to the progression of HCC. Liver cancer stem cells (LCSCs) are believed be root cause phenotypic functional heterogeneity However, impact Kla on biological processes LCSCs remains poorly understood. Here enhanced glycolytic metabolism, lactate accumulation, elevated levels observed compared HCC cells. H3K56la was found closely associated with tumourigenesis stemness LCSCs. Notably, comprehensive examination lactylome proteome ALDOA K230/322 lactylation, which promoting Furthermore, this study demonstrated tight binding between aldolase A (ALDOA) dead box deconjugate enzyme 17 (DDX17), attenuated by ultimately enhancing regulatory function DDX17 maintaining This investigation highlights significance modulating its Targeting may offer promising therapeutic approach for treating

Language: Английский

Citations

33
Lysine lactylation in the regulation of tumor biology DOI
Zijian Yang,

Yingqi Zheng,

Qiang Gao

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(8), P. 720 - 731

Published: Feb. 22, 2024

Language: Английский

Citations

28
HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury DOI Creative Commons
Wansu Yu, Qiuyue Kong,

Surong Jiang

et al.

JCI Insight, Journal Year: 2024, Volume and Issue: 9(7)

Published: March 13, 2024

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes revascularization following myocardial infarction. Anaerobic glycolysis during ischemia well-studied, but the role aerobic early phase reperfusion incompletely understood. Lactylation Histone H3 (H3) an epigenetic indicator glycolytic switch. Heat shock protein A12A (HSPA12A) atypic member HSP70 family. In present study, we report that ischemia, HSPA12A was downregulated and flux decreased in cardiomyocytes. Notably, knockout mice exacerbated MI/R-induced decrease, cardiomyocyte death, cardiac dysfunction. Gain- loss-of-function studies demonstrated required to support survival upon hypoxia/reoxygenation (H/R) challenge, its protective effects were mediated by maintaining homeostasis for lactylation. Further analyses revealed increased Smurf1-mediated Hif1α stability, thus increasing gene expression maintain appropriate activity sustain lactylation reperfusion, ultimately improving attenuate MI/R injury.

Language: Английский

Citations

20
Lactylation in cancer: Current understanding and challenges DOI
Hongde Li, Linchong Sun, Gao Ping

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1803 - 1807

Published: Oct. 10, 2024

Language: Английский

Citations

20
Lactate and lactylation in cardiovascular diseases: current progress and future perspectives DOI
Wengen Zhu,

Siyu Guo,

Junyi Sun

et al.

Metabolism, Journal Year: 2024, Volume and Issue: 158, P. 155957 - 155957

Published: June 21, 2024

Language: Английский

Citations

16
Lactate and lactylation in cancer DOI Creative Commons
Jie Chen, Ziyue Huang,

Ya Chen

et al.

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

Citations

9