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Moonlighting functions of glucose metabolic enzymes and metabolites in cancer

Nature Reviews Cancer volume 25, pages 426–446 (2025)Cite this article

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Abstract

Glucose metabolic enzymes and their metabolites not only provide energy and building blocks for synthesizing macromolecules but also possess non-canonical or moonlighting functions in response to extracellular and intracellular signalling. These moonlighting functions modulate various cellular activities, including gene expression, cell cycle progression, DNA repair, autophagy, senescence and apoptosis, cell proliferation, remodelling of the tumour microenvironment and immune responses. These functions integrate glucose metabolism with other essential cellular activities, driving cancer progression. Targeting these moonlighting functions could open new therapeutic avenues and lead to cancer-specific treatments.

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Fig. 1: Enzymes and metabolites in the glycolysis and gluconeogenesis pathways.
Fig. 2: Regulation of gene transcription by glucose metabolic enzyme-mediated histone modifications.
Fig. 3: Regulation of gene transcription by glucose metabolic enzyme-mediated regulation of transcription factors.
Fig. 4: Regulation of autophagy by glucose metabolic enzymes and metabolites.
Fig. 5: Regulation of cellular senescence and cell death by glucose metabolic enzymes and metabolites.
Fig. 6: Regulation of immune responses by glucose metabolic enzymes and metabolites.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (82188102 and 82030074 to Z.L.; 82372816 to D.G.; 82203553 to Y.M.; 82002445 to G.Z.), the Ministry of Science and Technology of the People’s Republic of China (2020YFA0803300 to Z.L.) and the National Center of Technology Innovation for Biopharmaceuticals (NCTIB2022HS02006 to Z.L.). Z.L. is the Kuancheng Wang Distinguished Chair.

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  1. These authors contributed equally: Dong Guo, Ying Meng, Gaoxiang Zhao.

Authors and Affiliations

  1. Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Dong Guo, Ying Meng, Qingang Wu & Zhimin Lu

  2. Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China

    Dong Guo, Ying Meng, Qingang Wu & Zhimin Lu

  3. Department of Oncology, Cancer Institute of The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, China

    Gaoxiang Zhao

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  1. Dong Guo
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  2. Ying Meng
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  4. Qingang Wu
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Contributions

D.G., Y.M., G.Z. and Z.L. researched data for the article. D.G., Y.M. and G.Z. contributed substantially to the discussion of the content. Z.L. wrote the article. D.G., Y.M., Q.W. and Z.L. reviewed and/or edited the manuscript before submission.

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Correspondence to Zhimin Lu.

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Glossary

Ataxia telangiectasia

A rare autosomal recessive genetic disorder characterized by progressive neurological degeneration (ataxia), telangiectasias (visible blood vessel abnormalities), immune deficiencies, increased cancer risk and hypersensitivity to ionizing radiation due to impaired DNA repair.

Autophagosome

A double-membrane vesicle that engulfs cellular components for degradation during autophagy.

Cytokinesis

The final stage of cell division in which the cytoplasm divides, resulting in two daughter cells.

Damage-associated molecular pattern

Molecules released by stressed or damaged cells owing to trauma or an infection by a pathogen, acting as endogenous danger signals and triggering an immune response.

Ectosomes

Extracellular vesicles released directly from the plasma membrane, made up of proteins, mRNAs and microRNAs, and involved in intercellular communication.

Homologous recombination

A DNA repair pathway that uses a homologous sequence as a template to accurately repair double-strand breaks.

Inflammasome

A cytosolic multiprotein complex that activates inflammatory responses and cell death by promoting cytokine maturation and pyroptosis.

Isomerization

A chemical reaction that rearranges molecules to form isomers, altering their structure without changing their molecular formula.

Kinetochore

A protein complex structure on the centromere of a chromosome that serves as the attachment site for spindle microtubules during cell division.

Lactylation

A post-translational modification involving the addition of a lactyl group to lysine residues on proteins, using lactyl-coenzyme A or lactate as an acylation donor.

Lipid droplet

Cellular organelles that store neutral lipids, such as triglycerides and cholesterol esters, for energy storage, membrane formation and protection from lipotoxicity.

Lipolysis

The breakdown of stored lipids to release free fatty acids and glycerol for energy metabolism.

Liquid–liquid phase separation

The process by which biomolecules spontaneously separate into highly concentrated liquid-like droplets, giving rise to membraneless organelles.

Mitochondrial fission

The division of a mitochondrion into two separate mitochondrial organelles, essential for cellular energy regulation and quality control.

Mitophagy

A selective form of autophagy in which damaged or dysfunctional mitochondria are degraded to maintain cellular health.

Non-homologous end joining

(NHEJ). A DNA repair pathway that fixes double-strand breaks by directly ligating the broken DNA ends without requiring a homologous sequence as a template.

Oxidative phosphorylation

A mitochondrial process in which ATP is produced using energy from electrons transferred through the electron transport chain.

Pattern recognition receptor

Immune receptors that recognize pathogen-associated molecular patterns or damage-associated molecular patterns to initiate immune responses.

Pentose phosphate pathway

(PPP). A metabolic pathway parallel to glycolysis that generates NADPH and ribose-5-phosphate for antioxidant reactions and nucleotide biosynthesis.

Serotonylation

A post-translational modification in which serotonin is covalently attached to glutamine residues within proteins, driven by transglutaminases, and affecting protein function and cellular signalling.

S-nitrosylation

A post-translational modification that occurs when nitric oxide covalently attaches to a cysteine thiol group on a protein to form an S-nitrosothiol, regulating protein function and cellular signalling.

Succinylation

A post-translational modification in which a succinyl group is added to lysine residues, driven both enzymatically and non-enzymatically, altering protein function and activity.

Sulfhydration

A modification involving the addition of hydrogen sulfide to cysteine residues in proteins, affecting their activity and stability.

Sumoylation

A post-translational modification in which small ubiquitin-like modifier (SUMO) proteins are attached to lysine residues of target proteins, influencing their activity and stability.

Telomere

Protective DNA–protein structures at the ends of chromosomes that prevent genomic instability during replication.

Transnitrosylation

The transfer of a nitric oxide group between proteins, driven both enzymatically and non-enzymatically, regulating protein conformational changes, activity, intracellular trafficking and protein–protein interactions.

Tricarboxylic acid (TCA) cycle

A central metabolic pathway that generates energy by oxidizing acetyl-coenzyme A into carbon dioxide and producing NADH and FADH2 for ATP synthesis.

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Guo, D., Meng, Y., Zhao, G. et al. Moonlighting functions of glucose metabolic enzymes and metabolites in cancer. Nat Rev Cancer 25, 426–446 (2025). https://doi.org/10.1038/s41568-025-00800-3

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