Chronic Alcohol Consumption Impairs Liver Regeneration by Disrupting RNA Splicing

Recent research conducted by scientists from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago has shed light on how long-term alcohol use impairs the liver's capacity to regenerate. The study reveals that excessive alcohol intake puts liver cells into a transitional, unproductive state, preventing proper regeneration even after cessation of drinking. This dysfunctional state results from inflammation-driven disruptions in RNA splicing, a critical process in protein production.

Key findings demonstrate that damaged liver cells in alcohol-related liver disease fail to complete their reprogramming to a regenerative state. Instead, they remain in a limbo phase, neither fully functional nor proliferative, which adds stress to the remaining healthy cells and exacerbates liver failure. Researchers identified widespread RNA missplicing affecting thousands of genes in diseased livers, notably caused by a deficiency of the protein ESRP2. This deficiency leads to mislocalization of proteins essential for regeneration, trapping them outside the nucleus where they are supposed to function.

The study further confirmed that inflammation factors released by support and immune cells in the damaged liver suppress ESRP2 production, hindering the splicing process. In experiments with mice lacking ESRP2, similar liver regeneration failure was observed, supporting the theory that ESRP2 deficiency plays a central role. Researchers suggest that targeting inflammation pathways to restore proper RNA splicing could open new therapeutic avenues.

This groundbreaking research enhances our understanding of the molecular mechanisms behind alcohol-associated liver disease, a leading cause of global liver-related deaths, and offers promising strategies for future treatments aimed at restoring liver function and promoting regeneration.