Novel Enzyme Discovery Offers Hope for Halting Fatty Liver Disease Progression

Researchers co-led by Cedars-Sinai have identified a protective enzyme that could help shield the liver from damage as metabolic dysfunction-associated steatotic liver disease (MASLD) progresses. The findings, published in Nature Metabolism, stem from a preclinical study and could pave the way for novel strategies aimed at preventing severe liver injury and liver failure.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, affects an estimated 100 million people in the United States, according to the American Liver Foundation. Among these individuals, roughly 20% to 25% develop metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of the disease characterized by liver fat alongside inflammation, cellular injury, and scarring.

Why MASH Is Difficult to Treat

Managing MASH currently focuses on lifestyle modifications and preventing further liver damage. While some therapeutic options exist, treatment choices remain limited, and there is no definitive cure for the condition.

Prior research has indicated that damaged mitochondria—the energy-producing powerhouses within cells—may drive the onset and worsening of MASH. In this new multicenter investigation, scientists at Cedars-Sinai discovered that levels of an enzyme known as UBE2N decline within liver cells as the disease advances.

“The UBE2N enzyme appears to protect the liver from the inflammation and damage associated with MASH by helping clear away compromised mitochondria and facilitating fat breakdown,” said Ekihiro Seki, MD, PhD, professor of Medicine and Biomedical Sciences at Cedars-Sinai and co-corresponding author of the study. “As enzyme levels dropped, we observed increased cellular damage and heightened liver injury.”

Restoring UBE2N Mitigates Liver Damage in Mice

To explore this potential therapeutic pathway, the research team restored UBE2N levels to normal in the livers of laboratory mice. This intervention led to noticeable reductions in fat buildup, inflammation, and scarring.

These compelling results indicate that UBE2N could serve as a promising therapeutic target for preventing the progression of MASLD to MASH.

“Identifying this enzyme’s role in hepatic mitochondrial regulation represents a significant step forward in understanding steatotic liver disease,” said Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Upcoming investigations should assess whether enhancing this protective mechanism can synergize with existing therapies, identify responsive patient populations, and foster innovative treatments to halt advanced liver disease.”

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