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 as the most common form of liver disease becomes more severe. The findings, from a preclinical study published in nature metabolismcould eventually support new strategies to prevent severe liver injury and progression to liver failure.
An estimated 100 million people in the U.S. have metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease, according to the American Liver Foundation. Approximately 20% to 25% of those affected develop metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of the condition in which excess liver fat is accompanied by inflammation, cellular damage and scarring.
Why MASH is difficult to treat
Current focus is primarily on lifestyle changes and efforts to limit further liver damage. 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 to clear damaged mitochondria and promoting the breakdown of fat,” said Ekihiro Seki, MD, PhD, professor of Medicine and Biomedical Sciences at Cedars-Sinai and co-corresponding author of the study. “When the enzyme levels decreased, we saw more damaged cells and lesions in the liver.”
Restoration of UBE2N reduced liver damage in mice
The researchers then restored UBE2N to normal levels in the liver of laboratory mice. After doing so, they saw reductions in fat accumulation, inflammation, and scarring.
Those results suggest that UBE2N could become a potential treatment 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 the understanding of steatotic liver disease,” said Shelly Lu, MD, president of the Guild of Women in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Future studies can 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.
Additional 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 (grants no. RS-2025-02273102 and RS-2025-02603096), the Chungbuk Regional Innovation System & Education (RISE) program (grant no. 2025-RISE-11-014-03), the American Association for the Study of Diseases Pinnacle Research Award Liver Diseases (AASLD, to JL), the San Diego Digestive Diseases Research Center (SDDRC) Pilot/Feasibility Grant (NIDDK P30 DK120515, to JL), the National Institutes of Health (grants nos. R01DK085252, R01DK138591, and R01CA301632), and the National Natural Science Foundation of China (grant #82404726).