Researchers from Cedars-Sinai Health Sciences University and Texas A&M University have identified an enzyme and a protein that regulate severe fatty liver disease, uncovering potential new treatment targets for millions of Americans.
An estimated 100 million people in the U.S. have metabolic dysfunction-associated steatotic liver disease (MASLD), according to the American Liver Foundation. Roughly 20% to 25% of those individuals develop metabolic dysfunction-associated steatohepatitis, or MASH.
This progressive form of the condition features excess fat accumulation accompanied by inflammation, cell injury, and scarring that can lead to cirrhosis and liver failure.
UBE2N Enzyme Protects Mitochondrial Health
Levels of an enzyme called UBE2N decline in liver cells as the disease advances, according to a multicenter study published in Nature Metabolism. Previous research identified damaged mitochondria—the cellular structures responsible for producing energy—as a major driver of MASH.
Investigators recorded more damaged cells and increased liver injury when levels of the enzyme fell. To test if restoring the enzyme could reverse these effects, researchers brought UBE2N back to normal levels in the livers of laboratory mice.
The intervention produced measurable reductions in fat buildup, inflammation, and scarring.
Additional authors of the work 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, Michael Karin, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, and Yoon Seok Roh.
MAP4K4 Protein Drives Disease Progression
Dr. Adi Joshi and his team at the Texas A&M College of Veterinary Medicine and Biomedical Sciences found that levels of a protein known as MAP4K4 increase as liver disease advances. This makes the protein a central regulator of multiple disease-related processes.
Working with collaborators at the University of Oklahoma, the Texas A&M team tested an experimental small-molecule inhibitor called GPPD. This compound selectively blocks the protein’s activity rather than removing it entirely, aiming to preserve normal functions while slowing the disease.
Dr. Adi Joshi, via Tamu
National Grants Fund Liver Research
The UBE2N investigation received financial backing from the National Research Foundation of Korea under grant numbers RS-2025-02273102 and RS-2025-02603096, and the Regional Innovation System and Education program of Chungbuk under grant number 2025-RISE-11-014-03.
Other support included the Pinnacle Research Award of the American Association for the Study of Liver Diseases, the San Diego Digestive Diseases Research Center pilot and feasibility grant through NIDDK award P30 DK120515, National Institutes of Health grants R01DK085252, R01DK138591, and R01CA301632, and the National Natural Science Foundation of China under grant number 82404726.
These findings target a condition that affects up to 25% of the 100 million Americans living with MASLD.
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