Researchers co-led by Cedars-Sinai Health Sciences University have identified an enzyme that may help protect the liver from the damage that can occur as the most common form of liver disease becomes more severe. The findings, from a preclinical study published in Nature Metabolism, could eventually support new strategies for preventing serious liver injury and progression toward 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. Roughly 20% to 25% of those affected go on to develop metabolic dysfunction-associated steatohepatitis (MASH), a more serious form of the condition in which excess liver fat is accompanied by inflammation, cell injury and scarring.
Why MASH Is Difficult to Treat
Current care mainly centers on lifestyle changes and efforts to limit additional liver damage. Although medications are available, treatment options are still limited, and there is currently no cure for MASH.
Earlier 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 decline in liver cells as the disease becomes more advanced.
“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 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 fell, we saw more damaged cells and injury to the liver.”
Restoring UBE2N Reduced Liver Damage in Mice
The researchers then restored UBE2N to normal levels in the livers of laboratory mice. After doing so, they observed reductions in fat accumulation, inflammation and scarring.
Those results suggest that UBE2N could become a potential treatment target for preventing MASLD from advancing to MASH.
“The identification of this enzyme’s role in regulating mitochondria in the liver is an important advance 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. “Future studies can test whether enhancing this protective pathway can complement existing treatments, identify patients most likely to benefit and lead to new therapeutic approaches for preventing advanced disease.”
Additional 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 (grant nos. RS-2025-02273102 and RS-2025-02603096), Regional Innovation System & Education (RISE) programme of Chungbuk (grant no. 2025-RISE-11-014-03), the Pinnacle Research Award of American Association for the Study of Liver Diseases (AASLD, to J.L.), the San Diego Digestive Diseases Research Center (SDDRC) Pilot/Feasibility Grant (NIDDK P30 DK120515, to J.L.), the National Institutes of Health (grant nos. R01DK085252, R01DK138591 and R01CA301632) and the National Natural Science Foundation of China (grant no. 82404726).
