An enzyme keeps fatty liver from turning dangerous, and 100 million Americans have the disease

An estimated 100 million Americans have metabolic dysfunction-associated steatotic liver disease, or MASLD, the condition formerly called nonalcoholic fatty liver disease. Only a fraction of them progress to the inflamed, scarring form known as MASH, and a liver enzyme called UBE2N appears to be one of the things standing between the two outcomes.

Ekihiro Seki, MD, PhD, a professor at Cedars-Sinai in Los Angeles, led the work on the enzyme. In mice, restoring UBE2N to normal levels cut fat buildup, inflammation and scarring in the liver, and the study appeared in Nature Metabolism.

UBE2N and the mitochondria it clears away

UBE2N is a ubiquitin-conjugating enzyme, a protein that attaches small molecular tags to other proteins so the cell knows what to do with them. In the Nature Metabolism paper, titled “UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis,” the tagging in question is a K63-linked ubiquitin chain placed on a protein called p62. That tag helps liver cells haul away damaged mitochondria, the energy-producing structures that leak harmful signals when they wear out.

When the enzyme is missing, p62 piles up in the cell’s cytoplasm and a stress-response pathway called NRF2 becomes overactive. The paper links that chain of events to PANoptosis, a combined form of cell death that merges pyroptosis, apoptosis and necroptosis, and that kills liver cells and feeds inflammation.

“The UBE2N enzyme appears to protect the liver from inflammation and damage associated with MASH by helping remove damaged mitochondria and supporting the breakdown of fat,” Seki said in the Cedars-Sinai announcement of the work, which carries a September 23, 2026 date. Shelly Lu, MD, who directs the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai, is named alongside Seki as a corresponding author, and the multicenter effort was co-led by Cedars-Sinai Health Sciences University.

Mouse livers with and without UBE2N

The team worked with mice bred to lack UBE2N only in liver cells, and compared them with normal littermates fed a Western-style diet meant to mimic the fat-heavy eating that drives human disease. The animals missing the enzyme developed worse MASH. A third group lacked both UBE2N and p62, and that combination was used to test whether p62 was the link between the missing enzyme and the damage. Human liver cells from people with MASH were examined as well.

Putting UBE2N back to normal levels in mice produced the reductions in fat, inflammation and scarring that the Cedars-Sinai announcement describes. All of that is preclinical. The work shows what the enzyme does in mouse livers and in a set of human cells, not that raising it in a patient would slow the disease, and no drug aimed at UBE2N exists in the material the institution released.

The American Liver Foundation estimate behind 100 million

The prevalence number is not a finding of the enzyme study. The Cedars-Sinai announcement attributes it to the American Liver Foundation, and the foundation’s own fatty liver page is a little more cautious than a round 100 million: it says an estimated 80 to 100 million people in the United States have MASLD, and that about 20 to 25 percent of them will progress to MASH. The same page puts MASLD in roughly 24 percent of U.S. adults and MASH in about 1.5 to 6.5 percent of adults.

The National Institute of Diabetes and Digestive and Kidney Diseases gives a matching range on its definition and facts page, saying experts estimate that about 24 percent of U.S. adults have the condition formerly called NAFLD and that about 1.5 to 6.5 percent have the inflamed form. Those percentages are survey-based estimates and not a head count, which is why 100 million sits at the top of the foundation’s stated band instead of at a fixed midpoint.

The treatment landscape for MASH

Medicine already has one approved drug for the dangerous end of the spectrum. The FDA cleared resmetirom, sold as Rezdiffra, on March 14, 2024, and its approval announcement described it as the first medication approved for noncirrhotic NASH with moderate to advanced liver scarring, a group the agency put at an estimated 6 to 8 million people in the United States. In the 12-month trial analysis, 26 to 27 percent of patients on the 80-milligram dose reached NASH resolution, against 9 to 13 percent on placebo.

That gap between 100 million people with fatty liver and a drug label covering a few million with scarring is the space an enzyme like UBE2N could eventually matter in, if its protective role holds in people. Seki’s group has so far shown the pathway in mice and cultured human cells, and the Nature Metabolism paper is the document that would have to be followed by human data before the enzyme becomes more than a lead.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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