New Study Uncovers How Prostate Cancer Rewires Metabolism to Resist Treatment

Prostate cancer cells may rewire amino acid metabolism to maintain cholesterol production and resist hormone therapy, according to a preclinical study by researchers at Weill Cornell Medicine.

The study, published in Nature Metabolism on August 20, found that propionyl-CoA, a compound produced during the breakdown of the amino acids isoleucine and valine, can activate a pathway that helps prostate tumors adapt to hormone-deprived conditions.

Researchers found that more aggressive human prostate tumors had elevated levels of propionylcarnitine, a metabolite closely related to propionyl-CoA. Further experiments showed that propionyl-CoA adds a chemical modification called propionylation to SREBP2, a protein that controls cholesterol production.

Normally, SREBP2 increases cholesterol production when cholesterol levels are low and switches the process down when levels are sufficient. However, propionylation stabilizes SREBP2 and keeps cholesterol-producing genes active, allowing prostate cancer cells to bypass this normal metabolic brake.

The additional cholesterol can then be used to produce androgens, including testosterone and related male hormones. These hormones activate the androgen receptor, a major driver of prostate cancer growth, potentially allowing tumors to maintain hormone signaling despite treatments such as enzalutamide.

Researchers also found that propionyl-CoA levels increased when prostate cancer cells were deprived of male hormones in laboratory models, suggesting the pathway may serve as a survival mechanism during hormone therapy.

In mouse models, restricting isoleucine and valine slowed prostate tumor growth and reduced the spread of cancer cells to the lungs. In contrast, increasing propionyl-CoA promoted tumor growth and lung colonization.

The findings raise the possibility that drugs targeting enzymes involved in converting isoleucine and valine into propionyl-CoA could potentially help overcome hormone therapy resistance. Researchers also want to investigate whether carefully controlled dietary strategies could influence the pathway.

However, the dietary findings are preclinical, and there is currently no evidence that people with prostate cancer should restrict isoleucine or valine on their own. Clinical studies will be needed to determine whether targeting this metabolic pathway is safe and effective in patients.

REFERENCE: Li, Z., et al. (2026). Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. Nature Metabolism. DOI: 10.1038/s42255-026-01583-z.