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Acetyl-CoA metabolism in cancer
Open accessAbstract
Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology. Acetyl coenzyme A (acetyl-CoA) is a key metabolite in carbohydrate and lipid metabolism and plays a role in signalling through protein acetylation, and the dysregulation of these pathways is a hallmark of various cancers. In this Review, Guertin and Wellen give an overview of acetyl-CoA metabolism in health and in cancer and discuss emerging therapeutic strategies for targeting metabolic pathways involving acetyl-CoA.
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“acetylation relies on acetyl-CoA (Box 1, Figure I); a key node in various metabolic pathways which are commonly dysregulated in cancer [1–3].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [1]
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“Protein acetylation is intrinsically linked to metabolism due to its use of key metabolic intermediate acetyl-CoA [1,52].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [1]
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Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
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“Acetyl-CoA can then exit the mitochondria as citrate, which is subsequently converted back into acetyl-CoA by ATP citrate lyase to support lipid synthesis and protein acetylation 80 .”
Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis
Izzo, L., Trefely, S., Demetriadou, C., Drummond, J. M., Mizukami, T., Kuprasertkul, N., Farria, A. T., Nguyen, P. T., Murali, N., Reich, L. N., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf0115 · Cited by 140
“…exported from mitochondria into acetyl-CoA and oxaloacetate, and acyl-CoA short chain fatty acid synthase 2 (ACSS2), which condenses acetate with coenzyme A. Acetyl-CoA generated by these enzymes is used for de novo lipogenesis (DNL), as well as for acetylation in the nucleus and cytosol ( 1 – 3 ).”
Self-citationMASH: the nexus of metabolism, inflammation, and fibrosis
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Metadata
- Authors
- Guertin, D. A., & Wellen, K. E.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- University of Pennsylvania (US)
- Corresponding author
- Guertin, David A.
- Wellen, Kathryn E.
- Venue
- Nature Reviews Cancer
- Published
- 2023-01-19
- Volume
- 23
- Issue
- 3
- Pages
- 156-172
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC11137663
- OpenAlex
- W4317436153
- Cited by
- 303
- References
- 200
- Citations by year
- 2026: 85 · 2025: 120 · 2024: 69 · 2023: 29
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature reviews. Cancer (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA174761, R01CA248315, R01CA228339, R01CA262055)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK094004, R01DK116005, R01DK127175)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- acetyl-CoA metabolism, cancer metabolism, TCA cycle, fatty acid synthesis, isoprenoid biosynthesis, lysine acetylation, protein acetylation, metabolic signalling, stable isotope tracing
- MeSH terms
- Acetyl Coenzyme A, Animals, Disease Models, Animal, Humans, Neoplasms, Mice, Metabolic Networks and Pathways
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