ArticleGastroenterology2021
Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.
Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 117 citations in OpenAlex.
- Research progress on lysine acetylation (Review).International journal of molecular medicine · 2026Review
- SIRT5-Mediated Desuccinylation of ACAA2 Protects Against Calcium Oxalate-Induced Kidney Injury by Regulating Fatty Acid Oxidation to Suppress Mitochondrial Oxidative Injury and Ferroptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SIRT5 mediates the pro-osteogenic effects of estrogen through FDX1 demalonylation and cuproptosis inhibition in mesenchymal stem cells.Genes & diseases · 2026Article
- Autophagy modulation in cancer.Nature reviews. Drug discovery · 2026Review
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Harnessing human tumor organoids for cancer modeling and precision therapy.Protein & cell · 2026Review
- Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma.Cell death and differentiation · 2026Article
- KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.Cancer research · 2026Article
- A MUC1-ALIX complex regulates extracellular vesicle cargo loading with activated SRC to enhance pancreatic cancer progression.Cancer letters · 2026Article
- Beyond deacetylation: crosstalk mechanisms and context-dependent regulation of sirtuin non-classical enzymatic functions in disease.Molecular medicine (Cambridge, Mass.) · 2026Review
- Deciphering RTK-RAS and MAPK Pathway Dependencies in Gemcitabine-Treated Pancreatic Ductal Adenocarcinoma Through Conversational Artificial Intelligence.International journal of molecular sciences · 2026Article
- Review
- IL1βJournal of translational medicine · 2026Article
- Conversational Artificial Intelligence Agents-Enabled Dissection of RTK-RAS and MAPK Pathway Dependencies in Gemcitabine-Treated Pancreatic Ductal Adenocarcinoma (PDAC).medRxiv : the preprint server for health sciences · 2026Article
- GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies.Molecular biomedicine · 2026Review
- Differential regulation of SIRT5 activity by reduced nicotinic acid riboside (NARH).RSC chemical biology · 2026Article
- Processes and therapeutic perspectives of acylation modifications of lysine and cysteine in tumors.Cell communication and signaling : CCS · 2026Review
- Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.Current cancer drug targets · 2026Review
- Emerging Role of Sirtuins-Mediated Ferroptosis in Hepatocellular Carcinoma Progression: Mechanisms and Therapeutic Perspectives.Journal of hepatocellular carcinoma · 2026Review
34 more citing papers are in PubMed but not listed here.
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Authors and funding
31 authors at 9 institutions in 6 countries.
Funding
Abstract
BACKGROUND &
aimsSIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.
methodsPublished datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts.
resultsSIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine.
conclusionsCollectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.