Researchers co-led by Cedars-Sinai Health Sciences University have identified a crucial enzyme that may help safeguard the human liver from the progressive damage associated with the most common form of chronic liver disease. The preclinical findings, published in the journal Nature Metabolism, shed light on the cellular mechanisms driving severe liver injury and could eventually pave the way for novel therapeutic strategies designed to prevent liver failure in millions of patients.
The discovery centers on metabolic dysfunction-associated steatotic liver disease, commonly known as MASLD, which was previously referred to as nonalcoholic fatty liver disease. According to data from the American Liver Foundation, an estimated 100 million people across the United States live with MASLD, making it one of the most prevalent metabolic and hepatic conditions in the country. While many individuals live with the early stages of the disease without experiencing severe symptoms, roughly 20% to 25% of those affected eventually progress to a much more serious and aggressive condition.
That advanced stage is known as metabolic dysfunction-associated steatohepatitis, or MASH. In patients with MASH, the accumulation of excess fat in the liver is no longer benign; instead, it is accompanied by chronic inflammation, active cell injury, and progressive scarring, or fibrosis, which can ultimately lead to cirrhosis, liver failure, or the need for a liver transplant.
Why MASH Is Difficult to Treat
Despite the staggering number of people affected by MASLD and MASH, clinical management options remain notably constrained. Current medical care mainly centers on lifestyle modifications, such as adopting sustained dietary changes, increasing physical activity, and making concerted efforts to limit any additional factors that could exacerbate liver injury.
Although pharmaceutical options have begun to emerge, treatment choices are still limited, and there is currently no definitive cure for MASH. Physicians and researchers alike face significant hurdles in halting or reversing the inflammatory and fibrotic cascades that characterize the advanced stages of the disease.
To overcome these therapeutic roadblocks, scientists have increasingly turned their attention to the microscopic powerhouses within human cells: mitochondria. Earlier research strongly suggested that damaged or dysfunctional mitochondria—the specialized intracellular structures responsible for producing energy for cellular functions—play a critical role in driving the development and progression of MASH. When mitochondria fail to function correctly, they can release harmful reactive oxygen species, trigger cellular distress, and promote inflammation within hepatic tissue.
Building upon this foundational understanding, researchers in the new multicenter study sought to investigate the specific molecular regulators governing mitochondrial health in the liver. Their investigation led them to focus on an enzyme called UBE2N. Upon analyzing liver tissue samples and disease progression models, the research team discovered that levels of the UBE2N enzyme naturally decline in liver cells as steatotic liver 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
To test whether the loss of UBE2N was merely a byproduct of the disease or an active driver of liver pathology, the researchers conducted a series of experiments using laboratory models. Specifically, they restored UBE2N to normal, healthy levels in the livers of mice that were developing features of advanced liver disease.
Following the restoration of the enzyme, the research team observed remarkable improvements in the hepatic tissue. The treated mice exhibited significant reductions in fat accumulation within the liver, alongside marked decreases in inflammation and structural scarring. These pronounced physiological improvements demonstrated that maintaining or restoring UBE2N activity could effectively counteract the damaging mechanisms that fuel the transition from simple fatty liver disease to severe steatohepatitis.
These compelling preclinical results strongly suggest that UBE2N could represent a highly promising therapeutic target for future drug development. By intervening at the level of mitochondrial regulation and fat metabolism, medical researchers hope to design interventions that can successfully prevent MASLD from advancing into the destructive stages of 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."
The collaborative study brought together investigators from multiple prestigious institutions. Additional Cedars-Sinai authors who contributed to the research include Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, and Yoon Seok Roh.
The international research team also included 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.
The research was made possible through financial support from a variety of institutional and governmental funding bodies. These include the National Research Foundation of Korea under grant numbers RS-2025-02273102 and RS-2025-02603096, and the Regional Innovation System and Education (RISE) programme of Chungbuk under grant number 2025-RISE-11-014-03. Additional support was provided by the Pinnacle Research Award of the American Association for the Study of Liver Diseases awarded to J.L., the San Diego Digestive Diseases Research Center Pilot and Feasibility Grant under National Institute of Diabetes and Digestive and Kidney Diseases grant number NIDDK P30 DK120515 to J.L., the National Institutes of Health under grant numbers R01DK085252, R01DK138591, and R01CA301632, and the National Natural Science Foundation of China under grant number 82404726.