Cedars-Sinai scientists identify enzyme that may slow fatty liver disease's most dangerous stage

Cedars-Sinai researchers have identified an enzyme that appears to shield the liver from the most damaging stage of fatty liver disease, a discovery that could point toward new treatments for a condition affecting roughly a quarter of American adults. The preclinical findings, published in Nature Metabolism, show that an enzyme called UBE2N helps liver cells clear out damaged mitochondria and break down excess fat, and that losing it coincides with the shift from simple fatty liver to a far more dangerous inflammatory disease.

What the researchers found

The team, co-led by investigators at Cedars-Sinai Health Sciences University, tracked UBE2N activity across the progression of metabolic dysfunction-associated steatotic liver disease, or MASLD, the condition long known as nonalcoholic fatty liver disease. They found that UBE2N levels fall steadily as the disease advances toward metabolic dysfunction-associated steatohepatitis, or MASH, a more aggressive form marked by fat buildup, inflammation, cell injury and scarring.

In mouse models, restoring UBE2N to normal levels reduced fat accumulation, inflammation and fibrosis in the liver. The enzyme works by supporting two cellular cleanup processes: mitophagy, which clears out damaged mitochondria, and the breakdown of stored fat inside liver cells. When UBE2N activity dropped, the researchers observed more damaged cells and greater liver injury, suggesting the enzyme normally acts as a brake on the disease's progression rather than merely a bystander that declines alongside it.

Context: a disease that has outpaced treatment options

MASLD has become one of the most common chronic liver conditions in the United States, driven by rising rates of obesity and type 2 diabetes. According to the National Institute of Diabetes and Digestive and Kidney Diseases, about 24 percent of American adults have the condition in some form, and it is present in up to 75 percent of people who are overweight and more than 90 percent of those with severe obesity. The disease spans a spectrum, from fat accumulation with little damage to full-blown MASH, which can progress to fibrosis, cirrhosis, liver failure and liver cancer.

• Roughly 100 million people in the United States are estimated to have MASLD, according to Cedars-Sinai researchers.
• Between 20 and 25 percent of those cases progress to MASH, the more aggressive, scarring form of the disease.
• MASH patients face a heightened risk of liver-related death and of cardiovascular disease, already the leading cause of death among people with fatty liver disease.
• Until recently, no approved drug directly targeted the liver damage itself rather than the metabolic risk factors, such as weight or blood sugar, that drive it.

UBE2N belongs to a family of ubiquitin-conjugating enzymes that tag damaged proteins and organelles for disposal inside cells, a quality-control system that researchers have been mapping in growing detail as a potential source of liver-disease drug targets. This study adds UBE2N to a short list of such molecules now considered plausible footholds for new MASH therapies, distinguishing itself by pointing to a protective role rather than a disease-driving one.

The field currently has only one FDA-approved drug for MASH: resmetirom, cleared in March 2024 for patients with moderate-to-advanced liver scarring. That drug works through an entirely different route, activating a thyroid hormone receptor in the liver to improve fat metabolism, and in its pivotal trial resolved MASH without worsening fibrosis in 27 percent of treated patients, versus 10 percent on placebo. Because resmetirom targets only patients who already have significant scarring, researchers have continued to look for mechanisms, such as UBE2N's role in cellular cleanup, that might intervene earlier in the disease's course.

Who is affected and why it matters

Because early-stage MASLD rarely causes symptoms, many patients do not learn they have liver damage until the disease is advanced, often after a routine blood test or imaging scan flags abnormal liver readings. A molecular target that works through the liver's own cleanup machinery, rather than only through weight loss or glucose control, could open a different therapeutic route for patients whose disease keeps progressing despite lifestyle changes. Given how common MASLD has become, even a modest reduction in the share of patients who progress to MASH would affect a substantial number of people who currently have few pharmaceutical options once lifestyle intervention has failed.

"The UBE2N enzyme appears to protect the liver from the inflammation and damage associated with MASH by helping remove damaged mitochondria and supporting the breakdown of fat," said Dr. Ekihiro Seki, a co-corresponding author of the study at Cedars-Sinai.

Dr. Shelly Lu, who holds the Women's Guild Chair in Gastroenterology at Cedars-Sinai and is a senior author on the paper, described the finding as clarifying a specific mechanical role for the enzyme inside liver cells. "The identification of this enzyme's role in regulating mitochondria in the liver is an important advance in understanding steatotic liver disease," she said. The study's additional authors include Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya and Yoon Seok Roh.

What happens next

The findings are preclinical, drawn from laboratory and mouse studies rather than human clinical trials, and the researchers describe restoring UBE2N activity as a potential strategy rather than a ready treatment. Before any therapy reaches patients, scientists will need to confirm the mechanism in human liver tissue, determine whether a drug can safely and selectively boost UBE2N activity in the liver, and test whether the protective effect holds up over the years-long course of real-world disease progression rather than in the shorter timeframe of a mouse study.

The study's early coverage in the science press has already flagged the enzyme as a candidate worth tracking as the field searches for drugs that intervene earlier in the disease's course, before fibrosis and cirrhosis set in. Cedars-Sinai said further work will build on a broader program of liver disease and cancer research underway at the institution, examining how UBE2N interacts with other components of the cell's protein-disposal system. No clinical trial of a UBE2N-targeted therapy has yet been announced.