New research suggests that inflammation from alcohol-related damage traps liver cells in an unproductive state by disrupting RNA splicing.
Key facts
- •Alcohol-associated liver disease is linked to approximately 3 million deaths annually worldwide.
- •Researchers found that inflammation suppresses the production and activity of the protein ESRP2.
- •Mis-spliced proteins in diseased livers often remain in the cytoplasm instead of moving to the nucleus to perform their functions.
- •Mice lacking the gene for ESRP2 developed liver injury patterns similar to those seen in humans with advanced alcohol-associated hepatitis.
- •The study was published in the journal Nature Communications.
Scientists have discovered why the liver often fails to repair itself in patients with alcohol-associated hepatitis and cirrhosis, even after they stop drinking. Researchers from the University of Illinois Urbana-Champaign, Duke University, and the Chan Zuckerberg Biohub Chicago found that inflammation disrupts RNA splicing, leaving liver cells trapped in a non-functional state between mature and regenerative phases.
The Mechanism of Cellular Limbo
Under normal conditions, the liver regenerates by having mature cells revert to a progenitor state to multiply before maturing again. In alcohol-associated liver disease, this cycle breaks down. Cells begin the transition toward a regenerative state but become stuck, unable to function as adult cells or complete the process of becoming new tissue. This creates a cycle where remaining healthy cells face increased pressure to regenerate, only to risk becoming trapped in the same unproductive state.
RNA Splicing and ESRP2 Deficiency
The research team identified that this failure is driven by widespread errors in RNA splicing, a process essential for turning genetic instructions into functional proteins. Specifically, they found a deficiency in a protein called ESRP2, which normally ensures RNA is spliced correctly. Without sufficient ESRP2, key proteins are mis-spliced and fail to reach the cell nucleus, where they are needed to regulate gene activity and drive regeneration.
Potential for Future Treatments
The study linked the reduction of ESRP2 to inflammatory signals released in response to alcohol-related tissue damage. In laboratory cultures, researchers successfully blocked these inflammatory signals, which allowed ESRP2 levels to recover and RNA splicing to normalize. These findings suggest that future therapies could target these inflammatory pathways to restore liver function or use mis-spliced RNA as diagnostic markers for the disease.
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This article was independently rewritten by ManyPress editorial AI from reporting originally published by ScienceDaily.
