MUSC researchers are tackling MASH, or metabolic dysfunction-associated steatohepatitis, a liver disease affecting hundreds of millions worldwide. It is also a leading cause of liver transplantation, yet treatment options remain limited.
A new paper published in Nature partner journal (npj) Metabolic Health and Disease suggests that a widely used asthma medication, formoterol, could potentially offer a different therapeutic pathway altogether. Formoterol is a beta-2 adrenergic receptor agonist that has been prescribed for decades to open airways in conditions like asthma and chronic obstructive pulmonary disease.
The work began in an unusual way, during the course of kidney research. Researchers originally tested formoterol in mouse models of kidney injury to determine if the drug could improve the damage associated with diabetes. During those experiments, which were successful and published in the American Journal of Physiology, Renal Physiology in 2024, they noticed something they hadn't anticipated: The mice receiving the drug also appeared to have less liver fat.
"Kind of unexpectedly, we found that the liver damage also reversed," said Joshua Lipschutz , M.D., Division director of Nephrology and the Arthur Williams Endowed Chair in Nephrology. He is also the author of the study, conducted in collaboration with Jessica Hartman, Ph.D., and Don Rockey, M.D., at MUSC. Brennan Winkler, a Ph.D. student from the Lipschutz Lab, and Kristina Stayer, a Ph.D. student from the Hartman Lab, were co-first authors.
That surprise finding prompted a second line of research focused specifically on the liver and whether the same beta-2 pathway could influence metabolic disease across multiple organs.
What the study found
To test that question, the team used a high-fat diet mouse model designed to mimic MASH. In the follow-up study, treatment with formoterol was associated with reversal of the fatty liver.
"This actually reversed the pathology on multiple different levels," said Lipschutz.
The study also explored underlying pathways that may help to explain these changes. They found signs that the drug may influence how cells produce and use energy.
"It looked like formoterol was rescuing the injury by increasing mitochondrial biogenesis," he explained. "It kind of revs up the mitochondria so they work better."
To complement the findings, the team conducted a retrospective analysis of patients who were already prescribed beta-2 agonists for respiratory conditions. In this real-world data, use of the drugs was associated with significantly lower rates of several serious liver-related outcomes, including cirrhosis and all-cause mortality.
Why this matters for MASH treatment
MASH is the progressive form of fatty liver and represents the stage at which fat accumulation begins to drive ongoing liver injury. Over time, this can lead to fibrosis, cirrhosis, liver failure and ultimately the need for transplantation. Its prevalence is rising globally, along with increases in obesity and Type 2 diabetes, making MASH one of the most urgent liver diseases in terms of a long-term public health burden.
"At the time we started the study, there were no drugs approved to treat MASH," said Lipschutz.
There are now two approved therapies, resmetirom and semaglutide, which can improve liver markers but remain only moderately effective and have side effects.
"All the current drugs for diabetic nephropathy only slow progression, but they don't reverse the damage. This drug actually reversed the damage at the histologic, ultrastructural and functional levels," noted Lipschutz.
Formoterol is already an established medication, used for years in asthma and chronic obstructive pulmonary disease, with a well-established safety profile. If its metabolic effects are confirmed in humans, this existing track record would significantly speed up the path toward further development and testing.
"If you can repurpose something that's approved and already being used safely, that's kind of our dream as physician-scientists," he said.
Why the first trial targets kidney disease
Although the paper focuses on MASH, Lipschutz's current trial is enrolling patients with diabetic kidney disease. However, given that the incidence of MASH in patients with diabetic nephropathy is over 60%, this trial will also allow the investigators to determine the effect of formoterol on MASH, as both conditions stem from the same underlying metabolic dysfunction and are among the most common and life-threatening complications of diabetes.
"So it is a two-for-one study," he said.
Existing data in both diseases offered encouragement for moving forward: "In both cases, there were human retrospective data suggesting that this could be working."
What comes next
Several important questions remain before formoterol can be considered a treatment for MASH or diabetic kidney disease. The new liver findings are based largely on mouse models, and the human data is observational, showing associations rather than causation.
"Not everything that works in mice works in humans," Lipschutz pointed out.
Researchers also still need to determine practical questions, including what would be most effective dose for metabolic disease, whether inhaled delivery will be enough to affect the liver or kidneys in humans and how durable any benefits might be over time.
"No drug is completely safe. I always say to my patients, 'Anything strong enough to do good can do bad,'" said Lipschutz.
The clinical trial Lipschutz and his team are currently enrolling for is designed to start answering these questions. If that trial yields encouraging results, it could pave the way for a novel treatment in both diabetic kidney disease and MASH.
"If you could be treating them with a repurposed, relatively safe, inexpensive drug that could be a really good thing," he added.
For now, the work highlights the possibility that a decades-old asthma medication may have untapped potential as a metabolic therapy, illustrating how sometimes research in one area can open doors in another.
