Comprehensive review of histone lactylation: Structure, function, and therapeutic targets

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 225, P. 116331 - 116331

Published: May 29, 2024

Language: Английский

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Emerging mechanisms and promising approaches in pancreatic cancer metabolism

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)

Published: Aug. 1, 2024

Abstract Pancreatic cancer is an aggressive with a poor prognosis. Metabolic abnormalities are one of the hallmarks pancreatic cancer, and cells can adapt to biosynthesis, energy intake, redox needs through metabolic reprogramming tolerate nutrient deficiency hypoxic microenvironments. use glucose, amino acids, lipids as maintain malignant growth. Moreover, they also metabolically interact in tumour microenvironment change cell fate, promote progression, even affect immune responses. Importantly, changes at body level deserve more attention. Basic research clinical trials based on targeted therapy or combination other treatments full swing. A comprehensive in-depth understanding regulation will not only enrich mechanisms disease progression but provide inspiration for new diagnostic therapeutic approaches.

Language: Английский

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Sirtuin 5‐Mediated Desuccinylation of ALDH2 Alleviates Mitochondrial Oxidative Stress Following Acetaminophen‐Induced Acute Liver Injury

Advanced Science, Journal Year: 2024, Volume and Issue: 11(39)

Published: Aug. 19, 2024

Abstract Acetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development various diseases. However, its involvement APAP‐induced acute injury (AILI) remains unclear. The present study aimed to explore role SIRT5 AILI. expression dramatically downregulated by APAP administration mouse livers and AML12 hepatocytes. deficiency not only exacerbates inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, opposite pathological biochemical changes are observed mice with overexpression. Mechanistically, quantitative succinylome analysis site mutation experiments revealed that desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 maintained enzymatic activity ALDH2, resulting suppression inflammation Furthermore, succinylation ALDH2 abolished protective effect against AILI, AILI dependent on desuccinylation K385. Finally, virtual screening natural compounds Puerarin promoted desuccinylase further attenuated Collectively, showed SIRT5‐ALDH2 axis plays critical progression might be strategy for therapeutic intervention.

Language: Английский

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Role of succinylation modification in central nervous system diseases

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 95, P. 102242 - 102242

Published: Feb. 21, 2024

Language: Английский

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Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development

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

Published: Jan. 29, 2025

Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer a negatively charged four-carbon succinyl group to ϵ-amino lysine residues, mediated succinyl-coenzyme A. Recent studies have highlighted involvement succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), member sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside deacetylase function. To date, only limited number SIRT5 substrates identified. These mediate diverse physiological processes such as glucose oxidation, fatty acid ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation these activities can occur through either same activity acting on different distinct targeting substrate. Aberrant expression closely linked tumorigenesis disease progression; however, role remains controversial. exhibits dual functionalities: it promote tumor proliferation, metastasis, drug resistance, metabolic reprogramming, thereby oncogene; conversely, also inhibit cell growth induce apoptosis, functioning suppressor gene. This review aims provide comprehensive overview current research status SIRT5. We discuss structural characteristics regulatory mechanisms, compare functions with other family members, elucidate mechanisms regulating activity. Specifically, we focus modification progression, highlighting how desuccinylation modulates development delineating underlying involved.

Language: Английский

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CPT1A mediates succinylation of LDHA at K318 site promoteing metabolic reprogramming in NK/T-cell lymphoma nasal type

Cell Biology and Toxicology, Journal Year: 2025, Volume and Issue: 41(1)

Published: Feb. 11, 2025

Carnitine palmitoyltransferase 1A (CPT1A), a succinylating enzyme, is highly expressed in various malignant tumors and promotes tumor progression. Succinylation posttranslational modification that has been reported diseases, but its role NK/T-Cell lymphoma nasal type (ENKTL-NT) remains underexplored. In this study, bioinformatics analysis showed glycolytic major metabolic pathway ENKTL-NT as the expression of many related kinases are increased. CPT1A probably mediates process, indicated by GO-enrichment analysis. Studies was upregulated tissues, high associated with poor prognosis ENKTL-NT. promoted proliferation, colony formation, invasion process cells suppresses apoptosis. Mechanistically, succinylation LDHA at lysine 318 (K318), which increase protein stability final level LDHA. Both knockdown mutation (K318R) abolished cancer-promoting effects all, study reveals mechanism underlying via inducing reprogramming These findings might provide potential targets for diagnosis or therapy

Language: Английский

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A nicotinamide metabolism-related gene signature for predicting immunotherapy response and prognosis in lung adenocarcinoma patients

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e18991 - e18991

Published: Feb. 27, 2025

Background Nicotinamide (NAM) metabolism fulfills crucial functions in tumor progression. The present study aims to establish a NAM metabolism-correlated gene (NMRG) signature assess the immunotherapy response and prognosis of lung adenocarcinoma (LUAD). Methods training set validation (the GSE31210 dataset) were collected Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO), respectively. Molecular subtypes LUAD classified by consensus clustering. Mutation landscape top 20 somatic genes was visualized maftools package. Subsequently, differential expression analysis conducted using limma package, univariate, multivariate LASSO regression analyses performed on screened construct risk model for LUAD. Next, MCP-counter, TIMER ESTIMATE algorithms utilized comprehensively immune microenvironmental profile patients different groups. efficacy chemotherapy drugs evaluated TIDE score pRRophetic A nomogram created integrating RiskScore clinical features. mRNA expressions independent prognostic NMRGs migration invasion cells measured carrying out cellular assays. Results Two (C1 C2) classified, with C1 subtype showing worse than C2. three high mutation frequency C2 TTN (45.25%), FLG (25.25%), ZNF536 (19.8%). Four ( GJB3 , CPA3 DKK1 KRT6A ) used model, which exhibited strong predictive performance. High-risk group showed low cell infiltration, score, prognosis, this drug sensitivity Cisplatin, Erlotinib, Paclitaxel, Saracatini, CGP_082996. established an accurate diagnostic all high- expressed cells, silencing inhibited cells. Conclusion novel NMRG developed, contributing evaluation personalized treatment patients.

Language: Английский

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Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 3, 2025

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate possibility of regimens sensitized by inhibiting succinylation in patients cholangiocarcinoma from perspective post-translational modification. Our omics analysis reveals that PDHA1 lysine 83, key enzyme tricarboxylic acid cycle, alters PDH activity, modulates metabolic flux, and leads alpha-ketoglutaric accumulation tumor microenvironment. This process activates OXGR1 receptor on macrophages, triggering MAPK signaling MHC-II antigen presentation, which promotes immune escape progression. Moreover, show CPI-613 enhances efficacy gemcitabine cisplatin. Targeting may be promising strategy improve treatment outcomes warrants further clinical exploration.

Language: Английский

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KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2

Journal of Biochemical and Molecular Toxicology, Journal Year: 2025, Volume and Issue: 39(4)

Published: April 1, 2025

ABSTRACT Lysine succinyltransferase KAT3B plays a critical role in the progression of various cancers by modulating key metabolic pathways, including glycolysis. However, function and underlying mechanism glycolysis lung cancer (LC) remain to be further studied. We determined mRNA expression levels lysine succinyl‐modifying enzymes through qRT‐PCR. Protein succinylation status glycolysis‐related proteins PKM2, LDHA, ENO1 were analyzed via Western blot. Co‐immunoprecipitation immunofluorescence microscopy employed verify interaction between PKM2. Bioinformatics analysis predicted sites on which subsequently validated site‐directed mutagenesis. The effects PKM2 LC cell malignancy evaluated using CCK‐8, transwell migration, glucose uptake, lactate production, ECAR, OCR assays. A xenograft tumor model was utilized assess impact growth. confirmed augmentation LC, also correlated with advanced TNM stages elevated T patients. Conversely, knockdown suppressed growth, metastasis, glycolytic activity cells vitro, while inhibiting growth vivo. mediated at K298, suppression upon downregulation largely reversed upregulation KAT3B/PKM2 axis may novel target for therapy.

Language: Английский

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Sirtuin 5 (SIRT5) Suppresses Tumor Growth by Regulating Mitochondrial Metabolism and Synaptic Remodeling in Gliomas

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9125 - 9125

Published: Aug. 22, 2024

Sirtuin 5 (SIRT5) is increasingly recognized as a key regulator of cellular metabolism, which commonly dysregulated in cancer cells, resulting enhanced proliferation and tumor progression. To investigate the clinicopathologic implications SIRT5 dysregulation glioblastoma, we performed comprehensive analyses transcriptomic data functional verifications using vitro vivo glioblastoma models. We found that higher expression levels were associated with favorable prognosis glioma patients. Knockdown significantly cell growth. Our suggest its potential role regulating mitochondrial metabolism gliomas. Furthermore, also correlated synaptic remodeling pathways. findings indicate tumor-suppressive for extends beyond by it may function through modulating neuroplasticity. Understanding these interactions provides nuanced insights into multifaceted broader therapeutic this development novel treatment strategies.

Language: Английский

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