Lactate: A key regulator of the immune response DOI Creative Commons
Alba Llibre,

Salih Kucuk,

Atrayee Gope

et al.

Immunity, Journal Year: 2025, Volume and Issue: 58(3), P. 535 - 554

Published: March 1, 2025

SummaryLactate, the end product of both anaerobic and aerobic glycolysis in proliferating growing cells—with latter process known as Warburg effect—is historically considered a mere waste cell tissue metabolism. However, research over past ten years has unveiled multifaceted functions lactate that critically shape impact cellular biology. Beyond serving fuel source, is now to influence gene expression through histone modification function signaling molecule impacts wide range activities. These properties have been particularly studied context adaptive innate immune responses. Here, we review diverse roles regulation system during homeostasis disease pathogenesis (including cancer, infection, cardiovascular diseases, autoimmunity). Furthermore, describe recently proposed therapeutic interventions for manipulating metabolism human diseases.

Language: Английский

Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

24
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

19
Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses DOI Creative Commons

Qihang Zhao,

Qiang Wang, Qinghua Yao

et al.

Cell Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Abstract Immunometabolism is critical in the regulation of immunity and inflammation; however, mechanism preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) glycolysis branching pathway specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S -D-lactoylglutathione (SLG) accumulates cytosol directly induces d -lactyllysine modification proteins. This nonenzymatic lactylation SLG greatly facilitated nearby cysteine residue, as it initially reacts with to form reversible -lactylated thiol intermediate, followed SN -transfer lactyl moiety proximal lysine. Lactylome profiling identifies 2255 sites mostly cytosolic proteins activated macrophages, global protein structure analysis suggests proximity residue determines susceptibility lysine SLG-mediated -lactylation. Furthermore, preferentially enriched involved inflammatory pathways, -lactylation at 310 (K310) RelA attenuates transcriptional activity restore homeostasis. Accordingly, TTP-binding site mutation or overexpression GLO2 vivo blocks this feedback cells promotes inflammation, whereas genetic deficiency pharmacological inhibition restricts both vitro vivo. Importantly, dysregulation GLO2/SLG/ regulatory axis closely associated human phenotypes. Overall, our findings uncover an immunometabolic loop SLG-induced implicate promising target for combating clinical disorders.

Language: Английский

Citations

4
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

10
Palmatine Retards Calcific Aortic Valve Disease Progression Targeting Gapdh K263 Lactylation Interfering with Glycolytic Metabolism DOI

Jiaqin Wu,

Shunshun Wang, Qianqian Du

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

1
Insight into the roles of lactylation in macrophages: functions and clinical implications DOI

Min Shu,

Dingci Lu,

Ziyi Zhu

et al.

Clinical Science, Journal Year: 2025, Volume and Issue: 139(02), P. 151 - 169

Published: Jan. 1, 2025

Lactylation, a post-translational modification, has been linked to gene transcription regulation through epigenetic modulation in various pathophysiological processes. The lactylation regulatory proteins, known as writers, erasers, and readers, govern their dynamics by adding, removing, recognizing lactyl groups on proteins. Macrophages, cells of the immune system, maintain homeostasis, responding dynamically diverse internal external stimuli. Emerging researches unveil that lactylation, inducing macrophage activation polarization, affects functionality pathological conditions such inflammation, tumor microenvironment, fibrosis. Evidence progressively indicates lactate-driven alterations levels within macrophages can influence pathogenesis numerous diseases. This review aims systematically summarize research progress macrophages, explore its functions mechanisms which contributes pathology different disease phenotypes, propose future directions along with potential diagnostic therapeutic strategies.

Language: Английский

Citations

1
Linking macrophage metabolism to function in the tumor microenvironment DOI
Robbie Jin, Luke Neufeld, Tracy L. McGaha

et al.

Nature Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Language: Английский

Citations

1
Lactylation in cancer: metabolic mechanism and therapeutic strategies DOI Creative Commons
Ying Sui, Ziyang Shen, Zhenling Wang

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 20, 2025

Recent progress in cancer metabolism research has identified lactylation as a critical post-translational modification influencing tumor development and progression. The process relies on lactate accumulation the activation of lactate-sensitive acyltransferases. Beyond its role epigenetic regulation, emerged significant factor evolution, offering fresh opportunities for developing targeted therapies that transcend traditional approaches. This review explores growing importance biology highlights potential advancing diagnostic tools therapeutic strategies.

Language: Английский

Citations

1
Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials DOI Creative Commons
Yipeng He,

Tianbao Song,

Jinzhuo Ning

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(11)

Published: Oct. 25, 2024

Lactylation, a recently identified form of protein post-translational modification (PTM), has emerged as key player in cancer biology. The Warburg effect, hallmark tumour metabolism, underscores the significance lactylation progression. By regulating gene transcription and function, facilitates metabolic reprogramming, enabling tumours to adapt nutrient limitations sustain rapid growth. Over past decade, extensive research revealed intricate regulatory network underlying tumours. Large-scale sequencing machine learning have confirmed widespread occurrence sites across proteome. Targeting enzymes or pathways demonstrated promising anti-tumour effects, highlighting therapeutic potential this modification. This review comprehensively explores mechanisms cells microenvironment. We expound on application advanced omics technologies for target identification data modelling within field. Additionally, we summarise existing anti-lactylation drugs discuss their clinical implications. providing comprehensive overview recent advancements, aims stimulate innovative accelerate translation lactylation-based therapies into practice. KEY POINTS: Lactylation significantly influences metabolism regulation, contributing Advanced reveal shows promise enhancing drug efficacy overcoming chemotherapy resistance. outlines implications future directions oncology.

Language: Английский

Citations

5
Vaccine-based immunotherapy and related preclinical models for glioma DOI Creative Commons
Binghao Zhao, Longping Yao,

Maryam Hatami

et al.

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(10), P. 965 - 981

Published: July 15, 2024

Glioma, the most common primary malignant tumor in central nervous system (CNS), lacks effective treatments, and >60% of cases are glioblastoma (GBM), aggressive form. Despite advances immunotherapy, GBM remains highly resistant. Approaches that target antigens expedite development immunotherapies, including personalized tumor-specific vaccines, patient-specific selection, dendritic cell (DC) chimeric antigen receptor (CAR) T (TCR) cells. Recent studies show promising results treating lower-grade glioma (LGG), fostering hope for future immunotherapy. This review discusses vaccines against glioma, preclinical models immunological research, role CD4

Language: Английский

Citations

4