Texas A&M researchers discover promising therapy for fatty liver disease

Researchers at Texas A&M College of Veterinary Medicine and Biomedical Sciences have identified a potential new target and have developed a new compound that could potentially treat metabolic dysfunction-associated steatohepatitis (MASH). The compound has been shown in human tissues and a preclinical model to reduce fat buildup, inflammation, liver injury and scarring. The data were published in a recent paper in JHEP Reports.

MASH is the more serious form of metabolic dysfunction-associated steatotic liver disease (MASLD), a disease that causes the liver to swell and can lead to cirrhosis, liver cancer and liver failure. In children and young adults, cirrhosis due to MASH is linked to liver-related mortality and cardiovascular disease.

The American Liver Foundation estimates that between 1.5% to 6.5% of U.S. adults have MASLD. A study published in JAMA Network Open in early 2025 projected that the number of cases in the United States could increase from 14.9 million in 2020 to 23.2 million in 2050.

Just two therapies are available to treat MASH. The first was Madrigal Pharmaceuticals’ Rezdiffra (resmetirom), which was approved in March 2024. It launched with a wholesale acquisition price of $47,400 per year. In 2025, Rezdiffra generated almost $1 billion in sales.

Novo’s weight loss drug Wegovy (semaglutide) was approved for MASH in August 2025. Wegovy is also approved to reduce the risk of major cardiovascular events in people who are overweight.

Role of MAP4K4

Researchers at Texas A&M have focused on MAP4K4, a protein involved in several major biological pathways. It plays a role in cell signaling and cell movement, as well as inflammation. Because MAP4K4 plays a role in how cells grow and divide, it is a target for cancer and metabolic research.

The Texas A&M researchers have determined that MAP4K4 levels increased as MASH advanced, suggesting it could serve as a promising new target for therapy.

“MASH is a complex metabolic disorder and is orchestrated by alternations in multiple pathophysiological pathways,” Aditya Joshi, Ph.D., associate professor in VMBS’ Department of Veterinary Physiology & Pharmacology, said in a news release. “It’s important to target multiple hallmarks of MASH rather than just one, and GPPD appears to attenuate many of the changes that are elevated during the disease.

Joshi and his colleagues, along with researchers at the University of Oklahoma, tested GPPD, which is a small molecule that selectively blocks the activity of MAP4K4. In their studies, researchers treated mice that had been fed a high fat to simulate fatty liver disease with GPPD. They found that GPPD reduced fat accumulation, inflammation, liver injury and fibrosis in these mice. GPPD treatment also significantly reduced hepatic triglyceride and cholesterol.

“MAP4K4 is a master regulator that influences multiple biological pathways involved in fat accumulation and disease progression,” Joshi said. “GPPD is unique because it decreases the protein’s activity without changing its overall levels, which may help preserve its normal functions while still providing therapeutic benefit.”

By inhibiting the protein’s activity, researchers hope to minimize unintended side effects while still slowing disease progression. The research team also conducted toxicology studies and found no evidence of significant toxicity.

Researchers also tested GPPD in human liver tissue from five healthy controls and 20 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and no history of alcohol use. They found that MAP4K4 expression was higher in MASLD livers than in livers from healthy individuals.