Study: Enzyme May Help Protect Against Severe Liver Disease

A team of investigators co-led by Cedars-Sinai Health Sciences University has identified an enzyme that helps prevent the most common form of liver disease from progressing toward liver failure. Results of the preclinical study, published in Nature Metabolism, could point the way to new approaches for preventing serious organ damage.

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. About 20% to 25% will progress to metabolic dysfunction-associated steatohepatitis (MASH), a more aggressive form of the disease in which excess fat buildup in the liver leads to inflammation, cell damage and scarring.

Treatments focus on lifestyle changes and protecting the liver from further damage. Medications are available, but effective options remain limited and there is no cure for MASH.

Previous research pointed to damaged mitochondria, which power cells, as a driver of MASH. In the new multicenter study, Cedars-Sinai investigators found that levels of the UBE2N enzyme in liver cells decrease as liver disease progresses.

“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.”

When investigators restored the UBE2N enzyme to normal levels in the livers of laboratory mice, fat buildup, scarring and inflammation were reduced. The findings suggest that the enzyme could be a promising target for preventing MASLD from progressing 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).

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