Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease

A new study investigated why patients with alcohol-associated liver disease, such as severe alcoholic hepatitis or alcoholic cirrhosis, have impaired liver regeneration capacity even after cessation of alcohol consumption. Using multi-omics profiling (snRNA-seq and snATAC-seq) along with molecular analyses in human tissue and mouse models, the researchers identified that RNA splicing regulation is impaired, preventing hepatocytes (the liver's principal cells) from transitioning to proliferative progenitor states necessary to repair liver damage.

In particular, they found that RNA regulatory proteins (RBPs) such as ESRP2, PTBP, and members of the SR family exhibit altered expression in diseased livers, leading to errors in the splicing of key genes such as Tcf4 and Slk. These errors alter the nuclear localization of the proteins produced, interfere with essential signaling pathways such as WNT and Hippo, and contribute to an inflammatory microenvironment that suppresses regenerative functions.

Taken together, these findings indicate that misspliced RNAs are effective biomarkers for alcohol-associated liver disease, and targeting them could improve recovery in affected individuals.

rnaUMAP showing distinct cell populations identified from multiomic profiling at single-cell resolution from over 27,000 liver nuclei from 15 individuals (n = 5 each)

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https://www.nature.com/articles/s41467-025-63251-2