A drug designed to shut down fat production inside the liver could become a major new weapon against one of the world’s fastest-growing liver diseases.
Researchers at University of California San Diego School of Medicine reported that an experimental treatment called ION224 produced significant improvements in people with metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form of fatty liver disease strongly linked to obesity and type 2 diabetes. The condition can quietly progress for years before leading to cirrhosis, liver failure, or liver cancer.
The findings were published in The Lancet and drew attention because the drug attacks a biological pathway directly involved in liver fat buildup. Instead of simply helping patients lose weight or manage symptoms, ION224 targets the disease process itself.
How the Experimental Drug Works
ION224 blocks an enzyme known as DGAT2, which helps the liver produce and store fat. Scientists believe excess fat inside liver cells triggers inflammation, tissue damage, and scarring over time.
“This study marks a pivotal advance in the fight against MASH,” said Rohit Loomba, MD, principal investigator of the study and chief of the Division of Gastroenterology and Hepatology at UC San Diego School of Medicine.
“By blocking DGAT2, we’re interrupting the disease process at its root cause, stopping fat accumulation and inflammation right in the liver.”
Researchers say this approach is especially important because many current treatments for fatty liver disease mainly focus on weight loss. ION224 appeared to improve liver health even when patients did not lose significant weight, suggesting it may eventually work alongside popular GLP-1 weight loss medications and other therapies.
Clinical Trial Results Show Encouraging Improvements
The Phase IIb clinical trial enrolled 160 adults in the United States with MASH and mild to moderate liver fibrosis. Participants received monthly injections of ION224 at different doses or a placebo over a 51 week period.
Patients receiving the highest dose showed some of the strongest results. About 60% experienced meaningful improvements in liver health compared with those receiving placebo treatment. Researchers also reported that the medication was generally well tolerated, with no serious side effects tied to the drug.
The study is considered notable because it is the first to show that blocking DGAT2 with an antisense therapy can improve liver inflammation and fibrosis in people with MASH. Researchers said the treatment also avoided some side effects seen with other drugs targeting liver fat production, including dangerous increases in triglycerides.
A Growing Global Health Threat
MASH, formerly called nonalcoholic steatohepatitis (NASH), is part of a broader condition known as metabolic dysfunction-associated steatotic liver disease (MASLD). The disease is becoming increasingly common as obesity and diabetes rates continue to climb worldwide.
According to estimates cited by researchers, as many as one in four adults globally may have some form of fatty liver disease, while more than 100 million people in the United States are affected. Many people never realize they have the condition because symptoms often do not appear until serious liver damage has already developed.
In severe cases, liver scarring can progress to cirrhosis and liver failure, leaving transplantation as one of the only remaining treatment options.
Why Scientists Are Excited About DGAT2
Interest in DGAT2 has grown because the enzyme plays a major role in de novo lipogenesis, the process the body uses to create fat in the liver. Scientists increasingly view this pathway as a key driver of inflammation and fibrosis in MASH.
“This is the first drug of its kind to show real biological impact in MASH,” Loomba said.
“If these findings are confirmed in Phase III trials, we may finally be able to offer patients a targeted therapy that halts and potentially reverses liver damage before it progresses to life-threatening stages.”
The researchers also noted that future treatment strategies may involve combination therapies, pairing liver-targeted drugs like ION224 with medications that improve weight loss, insulin resistance, or metabolic health.
What Happens Next
The next step will be larger Phase III clinical trials designed to confirm the drug’s safety and effectiveness in a broader patient population before regulators consider approval.
The study authors included Erin Morgan, Keyvan Yousefi, Dan Li, Richard Geary, and Sanjay Bhanot from Ionis Pharmaceuticals, along with Naim Alkhouri from Arizona Liver Health.
Funding for the research came from Ionis Pharmaceuticals (ION224-CS2).