Daijiworld Media Network – Chicago

Chicago, Sep 30: Researchers from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago have uncovered why long-term heavy drinking can leave the liver unable to repair itself—even after alcohol use stops—offering hope for new therapies beyond liver transplants.

The liver’s unique regenerative ability allows it to rebuild tissue after injury, but alcohol-related liver disease (ARLD) can leave liver cells stuck in a “limbo” state. These cells are neither fully mature nor stem-like, making them unable to regenerate tissue effectively. This semi-functional state places extra stress on remaining healthy cells, causing the liver’s repair system to falter.

The study also identified problems with RNA splicing—the process that edits genetic instructions for protein production. In damaged livers, the protein ESRP2, critical for proper RNA splicing, is missing. Without ESRP2, liver cells fail to receive correct “repair instructions,” halting regeneration. Mouse studies confirmed that absence of ESRP2 leads to similar liver damage as seen in humans.

Inflammation worsens the situation. Immune and support cells release chemicals that suppress ESRP2, compounding the damage. In lab experiments, blocking one inflammatory pathway restored ESRP2 levels and fixed RNA splicing, pointing to potential therapeutic strategies.

“We knew that the liver stops functioning and stops regenerating in patients with alcohol-related hepatitis and cirrhosis, even after they quit drinking, but we didn’t know why,” said U. of I. biochemistry professor Auinash Kalsotra, co-leading the study with Duke University professor Anna Mae Diehl. “Understanding this could help us intervene before liver failure, offering alternatives to transplantation.”

The findings pave the way for future treatments that could reduce liver inflammation, restore RNA splicing, and promote healing—even after years of heavy drinking, offering hope for millions affected by ARLD.