Chronic Alcoholism ceases Liver Cell Regeneration.

Sept 2025 : Excessive alcohol consumption can disrupt the liver’s unique regenerative abilities by trapping cells in limbo between their functional and regenerative states, even after a patient stops drinking, researchers at University of Illinois Urbana-Champaign and collaborators at Duke University and the Chan Zuckerberg Biohub Chicago describe in a new study. This in-between state is a result of inflammation disrupting how RNA is spliced during the protein-making process, the researchers found, providing scientists with new treatment pathways to explore for the deadly disease.

The liver has a remarkable ability to regenerate itself after damage or partial removal. However, it loses that ability in patients with alcohol-associated liver disease, which is the leading cause of liver -related mortality worldwide, resulting in roughly 3 million deaths annually.

“We knew that the liver stops functioning and stops regenerating in patients with alcohol-related hepatitis and cirrhosis, even when a patient has discontinued consuming alcohol, but we didn’t know why“, said Urbana of Illinois biochemistry professor Auinash Kalsotra, who co-led the study with Duke University School of Medicine professor Anna Mae Diehl. “The only real life-saving treatment option once a patient reaches the liver failure stage in those diseases is transplantation. But if we understood why these livers were failing, maybe we could intervene”.

Both, Kalsotra and Diehl have studied the molecular and cellular underpinnings of liver regeneration. Over the last five years, they found that in order to regenerate, liver cells reprogram their gene expression to revert to fetal-like progenitor cells, multiply and then reverse the process back to become mature functioning cells again. Armed with this knowledge, the group turned to the question of how those mechanisms were disrupted in alcohol-associated liver disease. Both the researchers have compared samples of healthy livers and samples of livers with alcohol-associated hepatitis or cirrhosis obtained from Johns Hopkins University Hospital.

The first thing the researchers noticed in diseased livers was that, although damaged cells had begun the process of reverting to the regenerative state, they did not complete the process and instead remained in transitional uncertainty. “They are neither functional adult cells nor proliferative progenitor cells. 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,” said Urbana of Illinois graduate students Ullas Chembazhi and Sushant Bangru, the co-first authors of the study.

To figure out why the cells were getting stuck in this state, the team investigated which proteins were being made by the liver cells and, in turn, the RNA molecules carrying the instructions for those proteins from the DNA to the cell’s protein-building machinery.

Kalsotra’s team used deep RNA sequencing technology and computational analyses to zoom in on the splicing of RNA fragments, a key step in stitching together different parts of genetic instructions to make proteins. “In comparing the samples, we saw RNA was getting mis-spliced broadly in alcohol-related liver disease, across thousands of genes, and it was affecting major functions of proteins“, said Kalsotra, who also is affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois.

The researchers found a possible driver of the RNA mis-splicing: Alcohol-damaged liver cells had a deficiency of the protein ESRP2, which binds to RNA to splice it properly. “Proteins function at a very specific place in the cell, and that is directed by sequences within the protein that take the protein to that particular spot. We found that, in many cases, the sequence that dictates where the protein localizes within a cell was mis-spliced. That’s why it was important that we did the multiple analyses we did“, said Kalsotra, also a member of the Chan Zuckerberg Biohub Chicago. “There was the same amount of RNA and protein, but the protein was not at the right place to function. Due to mis-splicing, key proteins that are required for productive liver regeneration were getting stuck in the cytoplasm, when they needed to be in the nucleus“.

To verify the culpability of ESRP2 deficiency, the researchers studied mice without the gene that produces ESRP2. They displayed similar liver damage and regeneration failure to that seen in patients with advanced alcohol-related hepatitis. But why was ESRP2 missing from liver cells from patients with alcohol-related hepatitis? Upon investigation, the researchers found that liver support cells and immune cells, drawn to the liver tissue damaged by alcohol processing, released high amounts of inflammatory and growth factors. Those factors suppress ESRP2 production and activity.

To authenticate, the researchers treated liver cell cultures with a molecule that inhibits the receptor for one of the inflammation-promoting factors. ESRP2 levels recovered and splicing activity was corrected, pointing to the pathway as a possible treatment target. “We can use these mis-spliced 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“, Kalsotra said.

Team Maverick