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Alcohol leaves the liver stuck in a state between damage and repair
Researchers have discovered why alcohol can leave persistent scars on the liver long after drinking stops. Researchers at the University of Illinois Urbana-Champaign, together with teams at Duke University and the Chan Zuckerberg Biohub Chicago, report that excessive alcohol exposure can trap liver cells in an intermediate, nonfunctional state that prevents normal regeneration. This dysfunction arises from inflammation-driven errors in RNA splicing that silence a key splicing regulator, blocking the normal cycle of cellular repair and maturation.
Alcohol-associated liver disease is a major global health problem, responsible for roughly 3 million deaths each year from conditions such as alcoholic hepatitis and cirrhosis. The liver normally regenerates by transiently reprogramming mature hepatocytes into proliferative, fetal-like progenitors, expanding cell numbers, and then returning them to their mature state. In severe alcohol-related disease, this reprogramming begins but does not finish: cells remain neither fully functional nor truly regenerative, creating a population of stalled cells that can accelerate organ failure.
Molecular mechanism: inflammation, missplicing, and ESRP2
To understand why regeneration fails, the research teams analyzed human liver samples from Johns Hopkins Hospital, collected under an initiative supported by the National Institute on Alcohol Abuse and Alcoholism. Rather than only comparing total RNA or protein levels, investigators used deep RNA sequencing and computational analyses to examine RNA splicing — the precise process that assembles messenger RNA (mRNA) segments into usable instructions for protein synthesis.
The results showed broad missplicing across thousands of genes in alcohol-damaged livers. Many affected mRNAs encoded proteins needed for cell localization and nuclear function. Although overall RNA and protein quantities sometimes appeared unchanged, missplicing altered sequences that normally direct proteins to their correct cellular compartments. As a result, important proteins remained misplaced in the cytoplasm instead of reaching the nucleus where they perform functions essential for regeneration.
A central finding was a deficiency of ESRP2, an RNA-binding protein that helps direct correct splicing for many liver genes. In alcohol-associated disease, ESRP2 levels were suppressed. Mouse models engineered to lack ESRP2 developed liver injury and regeneration failure resembling human alcohol-related hepatitis, supporting the idea that ESRP2 loss contributes directly to the stalled cell state.
How inflammation silences ESRP2
Further experiments showed why ESRP2 becomes reduced. Liver-supporting cells and infiltrating immune cells responding to alcohol damage release inflammatory cytokines and growth factors. Those signals downregulate ESRP2 production and impair its splicing activity, triggering wide-scale missplicing. In cultured liver cells, blocking the receptor for a key inflammatory factor restored ESRP2 levels and corrected splicing patterns, suggesting that interrupting this inflammatory signaling can re-enable productive regeneration.
Experimental approach and validation
The study combined human tissue analysis, genetic mouse models, cell-culture experiments, and high-depth RNA sequencing. Researchers contrasted healthy livers with samples from patients with alcohol-associated hepatitis or cirrhosis, then mapped splicing changes and protein localization shifts. Co-first authors Ullas Chembazhi and Sushant Bangru described the stalled cells as quasi-progenitors: neither adult functioning hepatocytes nor fully proliferative precursors.
To test causality, the team used mice lacking the Esrp2 gene and observed poor regeneration and progression to liver failure under stress, mirroring the human disease phenotype. Complementary cell-culture assays treated damaged liver cells with inhibitors of specific inflammatory pathways; when certain receptors were blocked, ESRP2 expression recovered and normal splicing resumed, allowing cells to progress past the stalled state.
Implications for diagnostics and therapy
These findings point to new therapeutic paths beyond transplantation. If inflammatory signaling drives missplicing and regeneration failure, then targeted anti-inflammatory or splicing-restorative treatments could help damaged livers recover. Misspliced RNAs themselves may also serve as diagnostic markers to identify patients whose livers are trapped in the nonproductive intermediate state and who may benefit from early intervention.
The study was published in Nature Communications and represents a multi-institutional effort to move from descriptive pathology to mechanism-based targets. Co-leader Auinash Kalsotra noted that understanding why livers fail provides a foundation for intervention — potentially enabling treatments that restore regenerative capacity in patients who have stopped drinking but continue to progress toward liver failure.
Future prospects and related technologies
Potential translational strategies include small-molecule inhibitors that block the inflammatory receptors suppressing ESRP2, biologics that neutralize specific cytokines, or RNA-targeted therapies that correct missplicing events. Advances in single-cell sequencing, spatial transcriptomics, and high-throughput splicing assays will accelerate identification of the most critical missplicing events and the cell types driving these signals. Gene-editing or RNA-modulating oligonucleotides could one day be used to restore proper splicing patterns in affected hepatocytes.
Clinical translation will require careful testing of safety and timing. Because inflammation plays protective roles in infection and tissue repair, selective modulation will be essential to avoid unintended immunosuppression. Nevertheless, the pathway identified offers a focused set of molecular targets where interventions might tip stalled cells back toward normal regeneration instead of irreversible failure.
Expert Insight
Dr. Mira Patel, a hepatologist and clinical researcher not involved in the study, comments: 'This work clarifies a long-standing clinical puzzle — why patients can stop drinking yet continue to decline. The mechanistic link between inflammation and RNA splicing opens an actionable window. In the near term, we should explore anti-inflammatory agents already approved for other diseases and assess their effect on splicing markers before moving to novel therapeutics.'
Conclusion
This research reveals that alcohol-associated liver disease can trap hepatocytes in an intermediate, nonfunctional state by triggering inflammation-driven RNA missplicing and loss of the splicing regulator ESRP2. The discovery explains persistent failure of liver regeneration after alcohol cessation and points to new diagnostic markers and therapeutic targets. By blocking specific inflammatory signals and restoring correct splicing, it may be possible to revive the liver's natural regenerative program and reduce the need for transplantation. Continued work with refined molecular tools and careful clinical evaluation will be required to translate these insights into safe, effective treatments.
Source: sciencedaily
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