Researchers co-led by Cedars-Sinai University of Health Sciences have identified an enzyme that may help protect the liver from damage that can occur when the most common form of liver disease worsens. The results of a preclinical study published in Natural metabolismcould potentially support new strategies to prevent severe liver damage and progression to liver failure.
According to the American Liver Foundation, approximately 100 million people in the United States have steatotic liver disease associated with metabolic dysfunction (MASLD), formerly called nonalcoholic fatty liver disease. About 20 to 25 percent of affected people develop metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of the disease in which excess liver fat is accompanied by inflammation, cell damage, and scarring.
Why MASH is difficult to treat
Current care focuses primarily on lifestyle changes and efforts to limit further damage to the liver. Although medications are available, treatment options are still limited and there is currently no cure for MASH.
Previous research has suggested that damaged mitochondria, the structures that produce energy for cells, may contribute to the development and progression of MASH. In the new multicenter study, Cedars-Sinai researchers found that levels of an enzyme called UBE2N decrease in liver cells as the disease progresses.
“The UBE2N enzyme appears to protect the liver from inflammation and damage associated with MASH by helping clear damaged mitochondria and promoting fat breakdown,” said Ekihiro Seki, MD, PhD, professor of medicine and biomedical sciences at Cedars-Sinai and co-corresponding author of the study. “When levels of the enzyme dropped, we saw more damaged cells and liver damage.”
Restoration of UBE2N reduces liver damage in mice
The researchers then restored UBE2N to normal levels in the livers of laboratory mice. After that, they observed a reduction in fat accumulation, inflammation and scarring.
These results suggest that UBE2N could become a potential therapeutic target to prevent MASLD from progressing to MASH.
“Identifying the role of this enzyme in regulating mitochondria in the liver is an important advance in understanding steatotic liver disease,” said Shelly Lu, MD, president of the Women’s Guild of Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Future studies will be able to test whether improving this protective pathway can complement existing treatments, identify patients most likely to benefit, and lead to new therapeutic approaches to prevent advanced disease.”
Other Cedars-Sinai authors include Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, and Yoon Seok Roh.
Other authors include: Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Xufeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, and Michael Karin.
Funding: This work was supported by the National Research Foundation of Korea (Grant No. RS-2025-02273102 and RS-2025-02603096), the Chungbuk Regional Innovation System & Education (RISE) Program (Grant No. 2025-RISE-11-014-03), the Pinnacle Research Award of the American Association for the Study of Liver Diseases (AASLD, to JL), the San Diego Digestive Disease Research Center (SDDRC) Pilot/Feasibility Grant (NIDDK P30 DK120515, to JL), the National Institutes of Health (Grant Nos. R01DK085252, R01DK138591, and R01CA301632), and the National Natural Science Foundation of China (Grant No. 82404726).
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