Targeting Fat Metabolism in Acute Myeloid Leukemia Stem Cells: The Therapeutic Potential of Avocadyne

Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancies, characterized by rapid disease progression and high relapse rates. Although many patients initially respond to chemotherapy, long-term remission is often undermined by a small population of leukemia stem cells (LSCs). These cells possess self-renewal capacity, resist standard treatments, and can reignite the disease after therapy. Understanding and targeting the unique survival strategies of AML stem cells has therefore become a central goal in modern leukemia research.

Researchers at the University of Colorado Anschutz Medical Campus, in collaboration with Canadian partners, have recently uncovered a surprising metabolic vulnerability in AML stem cells: their dependence on fat as an energy source. Traditional anti-leukemic therapies often aim to starve cancer cells by blocking their ability to utilize amino acids, which are critical for rapid cell growth and proliferation. However, the research team found that the most treatment-resistant AML stem cells are metabolically flexible. When deprived of amino acids, these cells adapt by switching to fatty acid oxidation as an alternative energy supply.

At the center of this metabolic switch is an enzyme known as very-long-chain acyl-CoA dehydrogenase (VLCAD), which plays a key role in breaking down long-chain fatty acids within mitochondria. AML stem cells were shown to rely heavily on VLCAD to sustain their energy needs under therapeutic stress. This discovery suggested that inhibiting fatty acid metabolism—rather than targeting traditional growth pathways alone—could selectively cripple the cells responsible for relapse.

To explore this possibility, the researchers conducted an innovative screening of existing compounds and identified avocadyne, a lipid molecule originally isolated from avocados. Avocadyne was found to inhibit VLCAD activity, effectively shutting down fatty acid oxidation in AML stem cells. By cutting off this critical energy source, avocadyne disrupted the metabolic foundation that allows these cells to survive when other nutrients are unavailable.

The preclinical results were striking. In mouse models of AML, avocadyne selectively eliminated leukemia stem cells while sparing healthy hematopoietic stem cells. This selectivity is particularly important, as damage to normal stem cells is a major cause of toxicity in current leukemia treatments. Furthermore, early clinical data from trials in diabetes research suggest that avocadyne is well tolerated in humans, strengthening its potential as a safe therapeutic candidate.

Importantly, this discovery does not aim to replace existing AML treatments but rather to complement them. Researchers believe avocadyne could be combined with therapies previously developed at CU Anschutz that already produce deep and lasting remissions in some patients. By adding a metabolic “second hit” that targets fat-dependent leukemia stem cells, such combination strategies may significantly reduce relapse rates.

In conclusion, this research identifies fatty acid metabolism as a critical Achilles’ heel of AML stem cells and highlights avocadyne as a promising new therapeutic agent. By targeting VLCAD and disrupting the metabolic adaptability of leukemia stem cells, this approach offers a novel and rational strategy to overcome treatment resistance. As human clinical trials for AML are now being planned, these findings provide renewed hope for improving outcomes in a disease that remains one of the most challenging forms of leukemia to treat (University of Colorado Anschutz Medical Campus, collaborative research report).