Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells DOI Creative Commons
Han Liu,

Yujie Hong,

Hui Chen

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 15(1), P. 278 - 295

Published: Nov. 27, 2024

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 (GLP1R) are both hormone receptors involved energy metabolism of epithelial cells. However, their role intestinal the underlying mechanisms remain largely unexplored. Herein GCGR GLP1R were found to be reduced stenotic ileum patients with Crohn's disease as well fibrotic colon mice chronic colitis. The downregulation led accumulation metabolic byproduct lactate, resulting histone H3K9 lactylation exacerbated through epithelial-to-mesenchymal transition (EMT). Dual activating by 1907B cells ameliorated vivo. We uncovered GCGR/GLP1R regulating EMT via lactylation. Simultaneously novel dual agonist holds promise treatment strategy for alleviating fibrosis.

Language: Английский

Unraveling the metabolic‒epigenetic nexus: a new frontier in cardiovascular disease treatment DOI Creative Commons
Jun Ouyang, Dong-de Wu,

Y. Gan

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 18, 2025

Abstract Cardiovascular diseases are the leading causes of death worldwide. However, there still shortcomings in currently employed treatment methods for these diseases. Therefore, exploring molecular mechanisms underlying cardiovascular is an important avenue developing new strategies. Previous studies have confirmed that metabolic and epigenetic alterations often involved across patients. Moreover, factors interact with each other affect progression a coordinated manner. Lactylation novel posttranslational modification (PTM) links metabolism epigenetics affects disease progression. analyzing crosstalk between cellular expected to provide insights development The purpose this review describe relationship heart such as failure, myocardial infarction, atherosclerosis, focus on acylation methylation, propose potential therapeutic measures.

Language: Английский

Citations

0
Role of lactylation and immune infiltration in atherosclerosis: novel insights from bioinformatics analyses DOI Creative Commons
Jin Qian, Qing Zhou

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 16

Published: April 3, 2025

The existing evidence indicates that atherosclerosis (AS) plays a pivotal role in the progression and exacerbation of cardiovascular diseases their associated complications. Current diagnostic therapeutic strategies for are limited ability to facilitate early detection personalized treatment. This study employs systems biology approach investigate lactylation-related genes (LRGs) pathogenesis atherosclerosis, while considering well-established correlation between inflammatory responses development. In this study, we utilized datasets obtained from Gene Expression Omnibus (GEO) as well data previous studies on (LRGs). Following this, identified 17 lactylation related associate with (AS-LRGs) GSE100927 dataset. Subsequently, employed validation dataset (GSE43292) assess these AS-LRGs, resulting identification 12 more reliable candidate genes. These were further analyzed functional enrichment through Ontology (GO) annotation, Kyoto Encyclopedia Genes Genomes (KEGG) pathway analysis, gene set analysis (GSEA). To elucidate potential utility AS-LRGs diagnosing high-risk plaques, assessed expression both late stages high- low-risk plaques. We then constructed interaction networks regulatory relationships among LRGs, miRNAs, transcription factors, drugs. Finally, single sample Set Enrichment Analysis (ssGSEA) method immune infiltration AS evaluate levels cell infiltration. reliably atherosclerosis: five upregulated (LSP1, IKZF1, MNDA, RCC2, WAS) seven downregulated (CSRP2, PPP1CB, CSRP1, HEXIM1, CALD1, PDLIM1, RANBP2). elucidates establishes robust foundation future research into targeted therapies clinical applications biomarkers.

Language: Английский

Citations

0
The emerging role of protein l-lactylation in metabolic regulation and cell signalling DOI

Haowen Ren,

Yuwei Tang, Di Zhang

et al.

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

Published: April 2, 2025

Language: Английский

Citations

0
PBertKla: a protein large language model for predicting human lysine lactylation sites DOI Creative Commons
Hongyan Lai, Dan Luo,

Mi Yang

et al.

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 6, 2025

Lactylation is a newly discovered type of post-translational modification, primarily occurring on lysine (K) residues both histones and non-histones to exert diverse effects target proteins. Research has shown that lactylation (Kla) modification ubiquitous in different cells participates the determination cell function fate, as well initiation progression various diseases. Precise identification Kla sites fundamental for elucidating their biological functions uncovering application potential. Here, we proposed novel human site predictor (named PBertKla) through curating reliable benchmark dataset with proper sample length sequence identity threshold train protein large language model optimal hyperparameters. Extensive experimental results consistently demonstrated our possessed robust prediction ability, achieving an AUC (area under receiver operating characteristic curve) value over 0.880 independent validation data. Feature visualization analysis further validated effectiveness feature learning representation from sequences. Moreover, benchmarked PBertKla against other cutting-edge models testing sources, highlighting its superiority transferability. All indicated excelled automatic sites, it would advance investigation modifications significance health disease.

Language: Английский

Citations

0
Semaphorin 6A phase separation sustains a histone lactylation–dependent lactate buildup in pathological angiogenesis DOI Creative Commons

Ya Ma,

Zhuyi Zhang,

Xiaolian Cao

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 17, 2025

Ischemic retinal diseases are major causes of blindness worldwide and characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts endothelial cells (ECs) suffice underlie excessive Lactate accumulation its subsequent histone lactylation ECs contribute vascular disorders. However, the regulatory mechanism establishing sustaining modification remains elusive. Here, we showed that lactate induced lactylations on H3K9 H3K18 neovascular proliferative stage oxygen-induced retinopathy. Joint CUT&Tag scRNA-seq analyses identified Prmt5 as a target H3K9la H3K18la isolated ECs. EC-specific deletion since early revascularization suppressed positive feedback loop production lactylation, thus inhibiting tuft formation. Mechanistically, C-terminal intrinsically disorder region (IDR) transmembrane semaphorin 6A (SEMA6A) forms liquid–liquid phase separation condensates recruit RHOA P300, facilitating P300 phosphorylation cycle. Deletion Sema6A reduced at promoter PRMT5 diminished expression. The induction SEMA6A-IDR pro-angiogenic effect were abrogated . Our study illustrates sustainable machinery driven separation-dependent lactyltransferase activation dysregulated vascularization.

Language: Английский

Citations

0
Lactylation as a metabolic epigenetic modification: Mechanistic insights and regulatory pathways from cells to organs and diseases DOI
Cong Chen, Jie Wang, Xueying Zhu

et al.

Metabolism, Journal Year: 2025, Volume and Issue: unknown, P. 156289 - 156289

Published: May 1, 2025

Language: Английский

Citations

0
Lactylation: A Novel Post-Translational Modification with Clinical Implications in CNS Diseases DOI Creative Commons
Junyan Liu, Fengyan Zhao, Yi Qu

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(9), P. 1175 - 1175

Published: Sept. 19, 2024

Lactate, an important metabolic product, provides energy to neural cells during depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription influences cell fate, processes, inflammation, immune responses. This review comprehensively examines regulatory roles mechanisms of neurodevelopment, neuropsychiatric disorders, brain tumors, cerebrovascular diseases. analysis indicates has multifaceted effects on system function pathology, particularly hypoxia-induced damage. Highlighting its potential novel therapeutic target, may play significant role treating neurological By summarizing current findings, this aims provide insights guide future research clinical strategies for disorders.

Language: Английский

Citations

1
Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells DOI Creative Commons
Han Liu,

Yujie Hong,

Hui Chen

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 15(1), P. 278 - 295

Published: Nov. 27, 2024

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 (GLP1R) are both hormone receptors involved energy metabolism of epithelial cells. However, their role intestinal the underlying mechanisms remain largely unexplored. Herein GCGR GLP1R were found to be reduced stenotic ileum patients with Crohn's disease as well fibrotic colon mice chronic colitis. The downregulation led accumulation metabolic byproduct lactate, resulting histone H3K9 lactylation exacerbated through epithelial-to-mesenchymal transition (EMT). Dual activating by 1907B cells ameliorated vivo. We uncovered GCGR/GLP1R regulating EMT via lactylation. Simultaneously novel dual agonist holds promise treatment strategy for alleviating fibrosis.

Language: Английский

Citations

1