New compound targets MAP4K4 pathway to combat fatty liver disease

Scientists have identified a potential new treatment target for metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of fatty liver disease affecting millions of people worldwide.

Researchers at the Texas A&M College of Veterinary Medicine and Biomedical Sciences have developed an experimental compound that reduced fat accumulation, inflammation, liver injury and scarring in preclinical models.

MASH develops when excess fat builds up in the liver, triggering inflammation and tissue damage. As the disease progresses, fibrosis can develop, potentially leading to cirrhosis, liver failure and the need for a transplant.

Although medicines for MASH have recently become available, they are currently intended for people with advanced disease and can cause side effects.

We have shown in our preclinical model that targeting the MAP4K4 pathway attenuates all of the major hallmarks of MASH. That gives us hope that this could eventually become a useful treatment option for patients, especially those who currently have very few therapeutic options.”

Dr Adi Joshi, Associate Professor in the Department of Veterinary Physiology and Pharmacology, Texas A&M

Targeting a key protein

Rather than focusing on the usual targets, the researchers investigated MAP4K4, a protein involved in several biological pathways linked to disease.

The team found that MAP4K4 levels increased as MASH progressed, suggesting the protein could play an important role in the development of the disease.

Working with researchers at the University of Oklahoma, the team tested GPPD, an experimental small-molecule inhibitor that blocks MAP4K4 activity rather than reducing the amount of protein in the body.

“MAP4K4 is a master regulator that influences multiple biological pathways involved in fat accumulation and disease progression,” Dr 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.”

Tackling several disease processes

The researchers found that GPPD improved several major features of MASH at the same time, including liver fat accumulation, inflammation, liver injury and fibrosis.

MASH involves multiple interconnected biological processes, meaning treatments targeting only one aspect of the disease may have limited effects.

“MASH is a complex metabolic disorder and is orchestrated by alternations in multiple pathophysiological pathways,” Dr Joshi 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.”

The study also identified a previously unknown signalling pathway through which MAP4K4 may influence the progression of MASH. The discovery could help researchers understand how the disease develops and identify additional therapeutic targets.

Path towards clinical trials

The experimental treatment showed an encouraging safety profile during preclinical testing. Researchers carried out toxicology studies and have so far found no evidence of significant toxicity.

Further pharmacokinetic studies are now being conducted to determine how the compound is absorbed, distributed and processed by the body. The results will help researchers establish appropriate doses before any potential human trials.

The team is also investigating whether GPPD improves liver disease directly or whether some of its effects are linked to weight loss observed during treatment.

If further studies are successful, the researchers hope the approach could eventually provide an option for people whose MASH 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,” Dr Joshi said. “If the clinical work is successful, I think it will really give hope to millions of patients living with this condition.”