ATP Citrate Lyase Inhibition in Cancer Metabolism

ATP citrate lyase (ACLY) catalyses the generation of cytosolic acetyl-coenzyme A (acetyl-CoA) from citrate, providing a pivotal link between carbohydrate catabolism and lipid synthesis. In malignant cells, ACLY activity is frequently elevated to satisfy demands for membrane biogenesis, energy storage and epigenetic regulation. Inhibition of this enzyme disrupts de novo lipogenesis, reduces histone acetylation and impairs oncogenic signalling pathways, thereby attenuating tumour growth and metastatic potential. Small-molecule inhibitors and genetic silencing have demonstrated efficacy in preclinical models across diverse cancer types, unveiling ACLY as a promising therapeutic target. Moreover, structural insights into its allosteric regulation have guided the design of more specific inhibitors. Integration of ACLY blockade with conventional chemotherapy and targeted agents may exploit metabolic vulnerabilities, offering a novel avenue for precision oncology.

Research from Nature Portfolio

Recent structural analyses have revealed an allosteric role for the central citrate synthase homology domain of ACLY, demonstrating how subtle conformational shifts control the binding and release of substrates and products. Mutation of a single residue within this region can trap a citryl-CoA intermediate, thereby preventing the formation of acetyl-CoA and highlighting a novel inhibitory strategy. In parallel, studies of metabolic regulation in high-grade ovarian cancer have identified a ubiquitin-specific peptidase that directly deubiquitinates and stabilises ACLY, reinforcing its central position in fatty acid synthesis and mitochondrial respiration. Targeting this deubiquitinase markedly suppresses tumour growth and sensitises cells to PI3K pathway inhibitors, underscoring the therapeutic potential of dual metabolic and signalling interventions.

ATP Citrate Lyase Inhibition in Cancer Metabolism publication trend

The graph below shows the total number of articles in atp citrate lyase inhibition in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

ATP citrate lyase (ACLY): Cytosolic enzyme that converts citrate to acetyl-CoA and oxaloacetate, supplying acetyl units for lipid synthesis and histone acetylation.

Acetyl-CoA: Central metabolite providing acetyl groups for fatty acid production and protein acetylation in gene regulation.

Allosteric regulation: Modulation of enzyme activity via binding of effectors at sites distinct from the active centre, altering conformation and function.

De novo lipogenesis: Biosynthetic pathway by which cells synthesise fatty acids from non-lipid precursors, essential for membrane formation and energy storage.

Deubiquitination: Enzymatic removal of ubiquitin tags from proteins, preventing their degradation and thus stabilising protein abundance.

Endoplasmic reticulum (ER) stress: Cellular condition triggered by accumulation of misfolded proteins in the ER, leading to adaptive signalling pathways that impact metabolism.

References

1. Allosteric role of the citrate synthase homology domain of ATP citrate lyase. Nature Communications (2023).
2. Amplification of USP13 drives ovarian cancer metabolism. Nature Communications (2016).
3. Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. Journal of Experimental & Clinical Cancer Research (2023).
4. Key Molecules of Fatty Acid Metabolism in Gastric Cancer. Biomolecules (2022).
5. IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell Death & Disease (2021).