ArticleHaematologica2023
Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
Article in Haematologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 22 citations in OpenAlex.
- Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Review
- Cholesterol Reprogramming in Acute Myeloid Leukemia: Integrating Tumor-Intrinsic Metabolism and Immune Crosstalk.Diseases (Basel, Switzerland) · 2026Review
- Peroxisomal Lipid Metabolism as a Therapeutic Target in Leukemia.Molecular nutrition & food research · 2026Review
- Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.Blood · 2026Article
- Jionoside B1 Sensitizes TNBC to Cisplatin by Inhibiting SIRT3-Mediated Oxidative Stress Defense.Biomedicines · 2026Article
- Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.Cell reports · 2025Article
- SIRT3-SUMO regulated Treg cell differentiation and asthma development by mediating N-glycosylation through the FAO pathway.Cell biology and toxicology · 2025Article
- Metabolomics of healthy hematopoietic stem cells and leukemic stem cells.Journal of clinical and translational research · 2025Article
- Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies.International journal of molecular sciences · 2025Review
- siRNA Mediated Genetic Perturbation of Primary Human Leukemia Stem and Progenitor Cells.bioRxiv : the preprint server for biology · 2025Article
- Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities.Leukemia · 2025Review
- Emerging roles for fatty acid oxidation in cancer.Genes & diseases · 2025Review
- The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia-A Promising Road Ahead.Cancers · 2025Review
- Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment.Molecular cancer · 2025Review
- Unraveling lipid metabolism for acute myeloid leukemia therapy.Current opinion in hematology · 2025Review
- Roles of SIRT3 in aging and aging-related diseases.International journal of biological sciences · 2025Review
- Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.Current pharmacology reports · 2024Article
- Metabolic dependencies of acute myeloid leukemia stem cells.International journal of hematology · 2024Review
- Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.Science translational medicine · 2024Article
- Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia.Biomarker research · 2024Review
Corrections and comments
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Authors and funding
27 authors at 5 institutions in 2 countries.
Funding
Abstract
Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.
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