Alcohol’s Unfortunate Side Effect

Published in Nature Communications, the findings point to a breakdown in RNA splicing during protein production, a process critical for healthy cell activity. This disruption prevents cells from completing the transition into a regenerative state, leaving the organ unable to heal.

Alcohol-associated liver disease is the leading cause of liver-related deaths worldwide, responsible for an estimated 3 million deaths every year.

While the liver is famous for its regenerative powers—even capable of regrowing after partial removal—those with advanced hepatitis or cirrhosis lose this ability.

As Professor Auinash Kalsotra of Illinois explained, “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. The only real life-saving treatment option once a patient reaches the liver failure stage is transplantation. But if we understood why these livers were failing, maybe we could intervene”

Kalsotra’s team, alongside Duke University’s Professor Anna Mae Diehl, compared healthy liver samples with those affected by alcohol-related disease. Their analysis revealed something striking: damaged cells had begun the process of shifting back toward regeneration but couldn’t complete the transformation.

Instead, they stalled in an intermediate stage. As graduate researchers, Ullas Chembazhi and Sushant Bangru described it, “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.”

To better understand why these cells were stuck, the team examined the proteins being produced. Using deep RNA sequencing, they uncovered widespread errors in RNA splicing across thousands of genes. In other words, the genetic instructions for building proteins were being stitched together incorrectly.

One key factor appeared to be a deficiency in ESRP2, a protein that normally ensures proper RNA splicing. Without ESRP2, many proteins essential for regeneration were misdirected within the cell—stuck in the cytoplasm when they should have been in the nucleus, where critical repair processes occur. Inflammation as the Culprit. Why was ESRP2 missing? The answer pointed back to inflammation.

The researchers found that immune and support cells recruited to alcohol-damaged liver tissue released inflammatory and growth factors that suppressed ESRP2. Without it, the regenerative machinery effectively broke down.

Follow-up experiments confirmed the link. When the team inhibited the receptor for one of these inflammation-promoting factors in liver cell cultures, ESRP2 levels rebounded and RNA splicing was restored. 

Toward Future Treatments

 The findings shed new light on why livers in patients with alcohol-related disease often fail to recover, even after alcohol use stops. More importantly, they suggest new therapeutic targets.

By addressing the inflammation that suppresses ESRP2 or by correcting the splicing defects directly, researchers may one day help restore liver function without the need for transplantation. As Kalsotra summarized, “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.”