Researchers at the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) have identified a new therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of fatty liver disease. The team developed an experimental compound that reduces fat buildup, inflammation, liver injury, and scarring in preclinical models, laying the groundwork for potential future patient trials.
MASH develops when excess fat accumulates in the liver, leading to inflammation, tissue damage, and fibrosis. This scar tissue buildup can eventually cause cirrhosis, liver failure, and the need for a transplant. While the first medications for MASH have recently become available, they are intended only for patients with advanced disease and have common side effects.
Dr. Adi Joshi, an associate professor in VMBS’ Department of Veterinary Physiology and Pharmacology, led the investigation into MAP4K4, a protein involved in several major biological pathways. The researchers determined that MAP4K4 levels increase as the disease advances, suggesting it could serve as a promising target. Working with collaborators at the University of Oklahoma, the team tested an experimental small-molecule inhibitor called GPPD.
Unlike other approaches that lower protein expression, GPPD selectively blocks the activity of MAP4K4. This method potentially preserves the protein’s normal functions while reducing its role in disease, which the researchers hope will minimize unintended side effects.
“We have shown in our preclinical model that targeting the MAP4K4 pathway attenuates all of the major hallmarks of MASH,” Joshi said. “That gives us hope that this could eventually become a useful treatment option for patients, especially those who currently have very few therapeutic options.”
