Promising therapy for fatty liver disease reduces fat, inflammation, and scarring in preclinical models
· Medical Xpressby Camryn Haines, Texas A&M University
edited by Lisa Lock, reviewed by Andrew Zinin
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For millions of people living with metabolic dysfunction-associated steatohepatitis (MASH), treatment options remain limited. The progressive form of fatty liver disease develops when excess fat accumulates in the liver, leading to inflammation, tissue damage and fibrosis—the buildup of scar tissue that can eventually cause cirrhosis, liver failure and the need for a transplant. Although the first medications for MASH have recently become available, they are intended only for patients with advanced disease and have common side effects.
Now, new research from the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) published in JHEP Reports has identified a promising therapeutic target and developed an experimental compound that reduces fat buildup, inflammation, liver injury and scarring in preclinical models, laying the groundwork for a potential new treatment.
"We have shown in our preclinical model that targeting the MAP4K4 pathway attenuates all of the major hallmarks of MASH," said Dr. Adi Joshi, an associate professor in VMBS' Department of Veterinary Physiology and Pharmacology. "That gives us hope that this could eventually become a useful treatment option for patients, especially those who currently have very few therapeutic options."
A new therapeutic target
Rather than focusing on traditional therapeutic targets, Joshi's team investigated MAP4K4, a protein involved in several major biological pathways. Because the protein acts as a central regulator of multiple disease-related processes, the researchers believed it could have broader effects on liver disease. They then determined that MAP4K4 levels increased as the disease advanced, suggesting it could serve as a promising new target for therapy.
Working with collaborators at the University of Oklahoma, the team tested an experimental small-molecule inhibitor called GPPD. Instead of lowering MAP4K4 expression, the compound selectively blocks its activity, potentially preserving the protein's normal functions while reducing its role in disease.
By inhibiting the protein's activity rather than removing it entirely, the researchers hope to minimize unintended side effects while still slowing disease progression.
"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."
Addressing multiple hallmarks of disease
The researchers found that GPPD improved several defining characteristics of MASH simultaneously, including fat accumulation, inflammation, liver injury and fibrosis.
Many experimental therapies focus on only one aspect of MASH, such as reducing fat buildup in the liver. However, researchers now recognize that the disease develops through several interconnected biological processes, meaning that successfully treating it requires addressing more than a single hallmark.
"MASH is a complex metabolic disorder and is orchestrated by alterations in multiple pathophysiological pathways," he said. "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."
In addition to demonstrating the compound's therapeutic effects, the team identified a previously unknown signaling pathway through which MAP4K4 appears to influence disease progression. Understanding how this pathway contributes to liver disease could help researchers identify additional therapeutic targets and better understand why MASH progresses over time.
Moving toward human trials
Beyond its effectiveness, the experimental therapy demonstrated an encouraging safety profile during preclinical testing. According to Joshi, the research team conducted extensive toxicology studies and, so far, has found no evidence of significant toxicity, an important milestone as the therapy moves closer to clinical testing.
Before the therapy can be tested in people, the researchers are completing pharmacokinetic studies to better understand how it is absorbed, distributed and processed by the body. These studies will help determine the safest and most effective dose for future clinical trials. They are also investigating whether the compound improves liver disease directly or whether some of its benefits result from the weight loss observed during treatment.
If those studies continue to produce promising results, Joshi believes the therapy could provide a much-needed option for patients whose disease has progressed beyond simple fat accumulation but has not yet reached its most severe stages.
"I think it's very important to identify novel targets against this disease," Joshi said. "If the clinical work is successful, I think it will really give hope to millions of patients living with this condition."
More information
Felix Ampadu et al, A novel pharmacological inhibitor of MAP4K4 activity attenuates metabolic dysfunction-associated steatohepatitis, JHEP Reports (2026). DOI: 10.1016/j.jhepr.2026.101886
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GastroenterologyClinical pharmacologyCommon illnesses & Prevention Provided by Texas A&M University Who's behind this story?
Lisa Lock
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