For years, scientists have known that the liver has a remarkable ability to regenerate. But in people with alcohol-associated liver disease, that healing process often stalls, leading to liver failure. Now, researchers from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago have uncovered why: damaged liver cells get stuck halfway through their transformation and can’t finish the job.
Excessive alcohol consumption can disrupt the liver’s unique regenerative abilities. It traps liver cells in a non-functional limbo, neither mature nor regenerative, even after drinking stops.
Usually, liver cells can reprogram themselves, temporarily reverting to a fetal-like state to multiply, then maturing back into fully functional cells. But when researchers compared healthy liver tissue to samples from patients with alcohol-associated hepatitis and cirrhosis, they saw something strange.
“They are neither functional adult cells nor proliferative progenitor cells,” explained University of Illinois graduate students Ullas Chembazhi and Sushant Bangru, co-first authors of the study. “Since they are not functioning, more pressure builds on the remaining cells. So they try to regenerate, and they’re all ending up in this unproductive quasi-progenitor state, and that’s what is causing liver failure.”
To understand why cells were getting stuck, the team looked at the proteins being made and the RNA instructions behind them. Instead of just measuring how much RNA or protein was present, they zoomed in on RNA splicing, the process of stitching together genetic instructions to build proteins.
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“In comparing the samples, we saw RNA was getting misspliced broadly in alcohol-related liver disease, across thousands of genes, and it was affecting major functions of proteins,” said Dr. Kalsotra, who is also affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois.
The culprit? A protein called ESRP2 helps splice RNA correctly. In alcohol-damaged livers, ESRP2 was missing. That led to proteins being built with the wrong instructions, especially the parts that tell them where to go inside the cell.
“There was the same amount of RNA and protein, but the protein was not at the right place to function,” said Kalsotra, also a member of the Chan Zuckerberg Biohub Chicago. “Due to missplicing, key proteins that are required for productive liver regeneration were getting stuck in the cytoplasm when they needed to be in the nucleus.”
To confirm ESRP2’s role, the team studied mice genetically engineered to lack the ESRP2 gene. These mice showed the same liver damage and regeneration failure seen in human patients.
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But why was ESRP2 missing in the first place? The researchers found that immune and support cells in the liver, activated by alcohol damage, were releasing inflammatory and growth factors that suppressed ESRP2.
To test a potential fix, the team treated liver cell cultures with a molecule that blocks one of these inflammation-promoting signals. ESRP2 levels bounced back, and RNA splicing improved.
“I’m hopeful these findings will become a launching pad for future clinical studies,” said Kalsotra. “We can use these misspliced RNAs as diagnostic markers or develop treatments that can curb the inflammation. And if we can correct the splicing defects, then maybe we can improve recovery and restore damaged livers.”
Journal Reference:
- Chembazhi, U.V., Bangru, S., Dutta, R.K. et al. Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease. Nat Commun 16, 8049 (2025). DOI: 10.1038/s41467-025-63251-2
