Researchers at the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago have identified a molecular mechanism that may explain why the liver fails to repair itself in advanced alcohol-associated liver disease, even after a patient stops drinking. The findings, published in Nature Communications, point to widespread RNA splicing errors driven by inflammation as a key driver of regenerative failure.
The liver is unusual among major organs in its capacity for regeneration. Under normal conditions, mature liver cells temporarily revert to a less specialised progenitor-like state, divide, and then mature again to restore damaged tissue. In alcohol-associated hepatitis and cirrhosis, the researchers found that this process stalls. Comparing healthy liver samples with diseased tissue, the team observed that cells had begun the transition toward a regenerative state but were unable to complete it, remaining trapped in an unproductive intermediate state that is neither functionally mature nor capable of proliferation. As more cells enter this state, the regenerative burden on remaining healthy cells increases, perpetuating a damaging cycle.
Deep RNA sequencing revealed that this cellular limbo is associated with widespread mis-splicing of RNA across thousands of genes. RNA splicing is the process by which genetic instructions are edited before being translated into proteins. In diseased liver cells, mis-splicing altered not only protein function but also the sequences directing proteins to their correct intracellular locations, leaving proteins required for regeneration stranded in the cytoplasm rather than reaching the nucleus.
The researchers traced the mis-splicing to a deficiency of a protein called ESRP2, which normally ensures accurate RNA splicing. Inflammatory signals generated during alcohol metabolism were found to suppress ESRP2 production and activity. In laboratory cultures, blocking one of these inflammatory signals restored ESRP2 levels and normalised splicing patterns, suggesting the pathway may be a potential therapeutic target.
Source: Chembazhi UV et al. Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease. Nature Communications (2025). DOI: 10.1038/s41467-025-63251-2
