Scientists from the University of Illinois at Urbana-Champaign, together with colleagues from Duke University, have uncovered why the liver loses its regenerative capacity after alcohol-related damage, even when alcohol use is discontinued. The study was published in Nature Communications (NatCom).

The liver is a unique organ capable of regenerating after injury. However, in cases of alcoholic hepatitis and cirrhosis, this mechanism fails, leaving liver transplantation as the only option once liver failure develops.

The researchers found that liver cells damaged by alcohol become “stuck” in a transitional state: they begin the process of transforming into regenerative progenitor cells but cannot complete it, leaving them non-functional.

 “They stop functioning as mature cells but also fail to become actively dividing progenitors. This creates increasing stress on the remaining healthy cells and ultimately leads to liver failure,” the authors explained.

The main cause was identified as defective RNA splicing, which is critical for proper protein assembly. The team discovered a deficiency of the protein ESRP2, responsible for ensuring correct RNA processing. As a result, proteins essential for regeneration are misplaced within the cell and lose their function.

In experiments, mice lacking ESRP2 developed the same defects seen in patients with severe alcoholic hepatitis. The researchers also found that inflammatory factors released by immune cells in damaged livers suppress ESRP2 production.

When liver cells were treated with a drug that blocked one of the inflammatory receptors, ESRP2 levels were restored and RNA function normalized. This opens the door to potential new therapies that could slow disease progression and restore the liver’s regenerative ability.