ArticleThe Journal of biological chemistry2020
Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 79 citations in OpenAlex.
- Sirtuins in Medicine: Multifaceted Roles in Physiological Processes and Cardiovascular Diseases.Biomolecules · 2026Review
- SIRT7 facilitates ferroptosis resistance of melanocytes via activating the SMAD3-ATF3-GPX4 signaling pathway in vitiligo.Journal of advanced research · 2026Article
- Friend or foe? The role of SIRT6 on macrophage polarized to M2 subtype in acute kidney injury to chronic kidney disease.Renal failure · 2025Review
- The Role of Sirt1 in Regulating Inflammatory Cytokines and Oxidative Stress in the Transition Mechanism from Depressive Disorder to Alzheimer's Disease.Molecular neurobiology · 2025Article
- Sirtuins as Endogenous Regulators of Cardiac Fibrosis: A Current Perspective.Cardiovascular toxicology · 2025Review
- The SIRT6 Activator MDL-800 Inhibits PPARα and Fatty acid Oxidation-Related Gene Expression in Hepatocytes.Biomolecules & therapeutics · 2025Article
- Atrial Cardiomyopathy-associated Arrhythmia and the Impact of Sirtuin Signaling Pathway: A Narrative Review.Current vascular pharmacology · 2025Review
- The dichotomic role of cytokines in aging.Biogerontology · 2024Review
- Role of AMPK and Sirtuins in Aging Heart: Basic and Translational Aspects.Aging and disease · 2024Review
- Expression and significance of SIRT6 in human peritoneal dialysis effluents and peritoneal mesothelial cells.International urology and nephrology · 2024Article
- SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs.Cardiovascular toxicology · 2024Review
- Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis.International journal of molecular sciences · 2024Review
- Exosomes derived from adipose tissue-derived stem cells alleviated HCell biology and toxicology · 2024Article
- SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging.Cellular and molecular life sciences : CMLS · 2024Review
- Dysregulation of histone deacetylases in ocular diseases.Archives of pharmacal research · 2024Review
- Research progress on the natural products in the intervention of myocardial infarction.Frontiers in pharmacology · 2024Review
- LncRNA MEG3: Targeting the Molecular Mechanisms and Pathogenic causes of Metabolic Diseases.Current medicinal chemistry · 2024Review
- TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis.Aging and disease · 2023Review
- Hepatocyte Sirtuin 6 Protects against Atherosclerosis and Steatohepatitis by Regulating Lipid Homeostasis.Cells · 2023Article
- Isolation and Culture of Primary Fibroblasts from Neonatal Murine Hearts to Study Cardiac Fibrosis.Bio-protocol · 2023Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor β (TGF-β) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-β signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-β signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-β signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.
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Registered trials
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.