Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease

Ullas V. Chembazhi, Sushant Bangru, Rajesh Kumar Dutta, Diptatanu Das, Brandon Peiffer, Subhashis Natua, Katelyn Toohill, Aurelia Leona, Ishita Purwar, Anuprova Bhowmik, Yogesh Goyal, Zhaoli Sun, Anna Mae Diehl () and Auinash Kalsotra ()
Additional contact information
Ullas V. Chembazhi: University of Illinois
Sushant Bangru: University of Illinois
Rajesh Kumar Dutta: Duke University Health System
Diptatanu Das: University of Illinois
Brandon Peiffer: Johns Hopkins University School of Medicine
Subhashis Natua: University of Illinois
Katelyn Toohill: University of Illinois
Aurelia Leona: Northwestern University
Ishita Purwar: University of Illinois
Anuprova Bhowmik: University of Illinois
Yogesh Goyal: Northwestern University
Zhaoli Sun: Johns Hopkins University School of Medicine
Anna Mae Diehl: Duke University Health System
Auinash Kalsotra: University of Illinois

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Individuals with progressive liver failure risk dying without liver transplantation. However, our understanding of why regenerative responses are disrupted in failing livers is limited. Here, we perform multiomic profiling of healthy and diseased human livers using bulk and single-nucleus RNA- and ATAC-seq. We report that in alcohol-associated liver disease, alterations in the hepatic immune milieu prevent hepatocytes from transitioning to proliferative progenitors. We also find differences in RNA binding protein expression, particularly of the ESRP, PTBP, and SR families, leading to misregulation of developmentally controlled RNA splicing. Our data pinpoint ESRP2 as a disease-sensitive splicing factor and support a causal role for its deficiency in the pathogenesis of severe alcoholic hepatitis. Notably, splicing defects in Tcf4 and Slk, two ESPR2 targets, alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways that are critical for normal liver regeneration. We further demonstrate that changes in stromal cell populations enrich failing livers with TGF-β, which suppresses the ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63251-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63251-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63251-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().