Metformin mimics exercise-related metabolic effects in prostate cancer patients

A new study has found that metformin, a widely prescribed diabetes drug, may mimic one of exercise's core biological effects in men with prostate cancer, raising levels of a molecule tied to energy balance and weight control even when patients are inactive. The findings suggest metformin could help counter the metabolic strain of hormone therapy, when fatigue and other side effects often limit physical activity.

Led by physician-scientists at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, the study appears in the journal EMBO Molecular Medicine.

Exercise is one of the most reliable ways to support health during cancer treatment. It helps regulate weight, blood sugar and cardiovascular health-factors that shape how patients feel during therapy and how well they recover afterward.

For many people with cancer, however, regular exercise isn't always feasible. Fatigue, hormone therapy, pain or advanced disease can limit physical activity precisely when metabolic health becomes most important.

That reality has led researchers to ask a practical question: if exercise confers its benefits through specific biological signals, could some of those signals be activated in other ways?

According to the research, the answer may be yes. Sylvester investigators report that metformin raises levels of a naturally occurring molecule involved in how the body manages energy and weight in prostate cancer patients.

The finding does not suggest that a pill can replace physical activity. Instead, it offers insight into the internal pathways that underlie exercise's metabolic benefits-and how those pathways might still be engaged when movement is limited.

This study reflects what's possible when laboratory science, metabolic biology and clinical investigation are intentionally brought together for transdisciplinary studies. By working across Sylvester's Tumor Biology, Cancer Epigenetics and Translational & Clinical Oncology programs, we were able to link a well-defined molecular signal to real patient data. The result isn't a new cancer biomarker, but a clearer understanding of how a widely used drug may support metabolic health during prostate cancer treatment-an outcome that matters to patients and clinicians alike."

Marijo Bilusic, M.D., Ph.D., Sylvester researcher and first author, genitourinary medical oncologist and professor of medicine and medical oncology at the Miller School

At the center of the collaborative, team-science study is a molecule called N-lactoyl-phenylalanine, or Lac-Phe. While its name is technical, its role is relatively simple.

Lac‑Phe is produced when the body is under metabolic demand. It forms when lactate-a substance that accumulates during exertion-combines with phenylalanine, a basic building block of protein. Scientists first took notice of Lac‑Phe because its levels spike after intense exercise, coinciding with shifts in energy use and appetite regulation.

In preclinical and early human studies, higher Lac‑Phe levels have been associated with reduced appetite and improved weight control-two effects commonly linked to regular physical activity.

Lac-Phe does not rise only with exercise. Scientists observed elevated ‑Lac-Phe‑ levels in people taking metformin, even in the absence of physical activity. That overlap raised an important question for cancer care: could a pathway typically associated with exercise be activated pharmacologically in patients whose treatments limit movement?

To explore that question, the Sylvester team focused on prostate cancer, where hormone-based therapies are known to disrupt metabolism, contributing to weight gain, insulin resistance, and cardiovascular risk.

Notably, Lac-Phe levels in patients treated with metformin‑ approximated those previously reported after strenuous exercise. This occurred even though patients were not exercising at the time of blood collection, and the effect persisted after hormone therapy began.

"From a clinical standpoint, seeing a metabolic signal that mirrors what we associate with intense exercise was striking," said Bilusic. "For patients whose treatments or symptoms limit physical activity, that kind of effect could be especially meaningful."

Higher Lac-Phe levels were not associated with anti-tumor response to metformin. The metabolite did not correlate with changes in prostate-specific antigen (PSA), a standard marker used to monitor‑ prostate cancer.

That distinction is central to the study's interpretation. While more expanded studies are needed to determine the utility of Lac-Phe as a marker of anticancer efficacy, it appears to reflect how the body manages energy, weight‑ and metabolic strain during treatment. These results were confirmed to ensure the findings were not limited to one clinical setting. In fact, increases were also observed in patients receiving other metabolic therapies, suggesting Lac-Phe may reflect a broader metabolic response rather than a drug‑specific effect.

"Cancer therapy often affects the body in ways that go beyond the tumor," said Sylvester researcher Priyamvada Rai, Ph.D., co-leader, Tumor Biology Program and professor of radiation oncology at the Miller School. "Supporting metabolic health can influence how patients tolerate treatment and how they feel over time, even if it doesn't directly change tumor growth. This study was an opportunity to investigate molecular pathways that can be therapeutically activated for better outcomes to treatments that induce metabolic stress."

Metformin raises a stress hormone called GDF‑15, but this study found that Lac‑Phe was more closely tied to weight changes. Because the two didn't rise together, metformin likely affects weight through multiple pathways, with Lac‑Phe playing a bigger role.

"Metabolism is involved in everything cells do," said Sylvester researcher David B. Lombard, M.D., Ph.D., co-leader, Cancer Epigenetics Program and professor of pathology and laboratory medicine at the Miller School. "These findings suggest Lac-Phe may be a very informative signal for understanding how metformin affects metabolism in prostate cancer patients."

Taken together, the findings offer a clearer picture of how a widely used diabetes medication may influence metabolic health during prostate cancer care.

"What's encouraging about this work is that it reminds us cancer care isn't only about targeting tumors-it's also about supporting the whole patient," said Rai. "By better understanding how treatments affect metabolism, we can begin to identify ways to help patients maintain strength, resilience and quality of life throughout their care."