Scientists have identified a biological trigger that helps explain why many people with cancer lose muscle during treatment, a discovery that could eventually lead to drugs to preserve strength and mobility.
The research, published April 25 in the Journal of Clinical Investigation, identifies an enzyme called MESH1 as a central driver of cancer cachexia — a condition marked by muscle loss, weakness, and fatigue. It affects up to half of patients with advanced cancer and is linked to poorer survival.
The team identified MESH1 as the long-sought enzyme that breaks down coenzyme A (CoA), a molecule essential for energy production and cellular stress protection. Early lab studies show muscle samples from patients with cancer-related muscle loss had elevated levels of the enzyme.
“Naming MESH1 as that enzyme turns CoA degradation into a regulated, druggable lever and our data show that lever is turned up in the muscle of those with cancer-related muscle loss,” said corresponding and senior study author Jen-Tsan Chi, PhD, a cancer biologist and professor in the Duke Department of Molecular Genetics and Microbiology.
In experiments using fruit flies, excess MESH1 depleted protective molecules and triggered ferroptosis, a form of cell death linked to oxidative damage.
“This gives us a tangible path to intervene and that’s something we didn’t have before,” said Chi, co-director of the Cancer Biology Program at Duke Cancer Institute.
First authors of the study include Duke researchers Chao-Chiech Lin, Joshua Rose, and Alexander A Mestre. Pei Zhou, PhD, professor of biochemistry at Duke School of Medicine, is also a corresponding author.
Future studies will examine if blocking the enzyme could prevent or reverse muscle wasting.
“This pathway helps explain why muscle becomes fragile in patients with cancer cachexia,” said co-corresponding author Hong-Wen Tang, PhD, an assistant professor in the Cancer & Stem Cell Biology Signature Research Programme at Duke-NUS Medical School, Singapore. “Understanding changes in components of the pathway could be key to restoring muscle strength and physical function.”
An enzyme with a double life
MESH1 wasn’t completely unknown before the study. Scientists already knew it breaks down another important molecule, NADPH, which helps protect cells from stress and damage.
What surprised researchers is that MESH1 does both jobs — breaking down NADPH and CoA — giving it powerful control over whether cells survive or die.
“Scientists still don’t fully understand how MESH1 manages to orchestrate so many metabolic pathways and signaling events at once,” Zhou said. “AI-based protein engineering of MESH1 may ultimately enable the design of variants with isolated functions, thereby facilitating mechanistic dissection of MESH1’s contribution to individual processes.”
The findings point to MESH1 as a promising drug target. In theory, inhibiting the enzyme could help maintain CoA levels and shield muscle tissue, even as patients receive aggressive therapies such as chemotherapy and radiation.
Cancer cachexia has long been difficult to treat. Nutritional support alone is often ineffective because the condition is driven by metabolic and inflammatory changes rather than lack of calories.
Current treatments are limited, and no drugs are approved in United States specifically to prevent cancer-related muscle wasting.
Researchers received support from the National Institutes of Health, Duke DCI Pilot Project, Department of Defense, Singapore’s Ministry of Education AcRF Award, Diana Koh Innovative Cancer Research Award, and the National Medical Research Council and Singapore Ministry of Health.