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Dysregulated signal transducer and activator of transcription 3 drives intestinal permeability and may contribute to acute-on-chronic liver failure
Nikolai Leinz, Sandra Beyer, Babithra Yoganathan-Kugarajan, Nico Kraus, Cristina Ortiz, Lisa Hahnefeld, Robert Gurke, Marion Başoğlu, Guido Plotz, Stefan Eimer, Stefan Zeuzem, Jonel Trebicka, Christoph Welsch, Angela Brieger
Nikolai Leinz, Sandra Beyer, Babithra Yoganathan-Kugarajan, Nico Kraus, Cristina Ortiz, Guido Plotz, Stefan Zeuzem, Christoph Welsch, Angela Brieger, Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt 60590, Hesse, Germany
Lisa Hahnefeld, Robert Gurke, Goethe University Frankfurt, Faculty of Medicine, Institute of Clinical Pharmacology, Frankfurt 60590, Hesse, Germany
Robert Gurke, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, Frankfurt 60590, Hesse, Germany
Marion Başoğlu, Stefan Eimer, Goethe University Frankfurt, Institute of Cell Biology and Neuroscience, Frankfurt 60590, Hesse, Germany
Jonel Trebicka, Department of Internal Medicine B, University Hospital Münster, Münster 48149, North Rhine-Westphalia, Germany
Author contributions: Leinz N and Beyer S performed the experiments; Hahnefeld L and Gurke R conducted the lipidomic analyses; Yoganathan-Kugarajan B assisted as laboratory technician; Başoğlu M assisted with electron microscopy; Eimer S evaluated the electron microscopy images; Ortiz C and Kraus N assisted with mouse tissue processing and staining; Leinz N contributed to manuscript writing and proofreading; Brieger A conceived and designed the study, wrote the manuscript; Trebicka J, Plotz G, Zeuzem S and Welsch C critically discussed the data and reviewed the manuscript.
Supported by LOEWE Research Program (Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz) of the State of Hessen (HMWK) within the ACLF- Research Initiative, No. ACLF-I; University Hospital Frankfurt “Programm Nachwuchswissenschaftler”; Verein Leberforschung Frankfurt e.V; and German Research Foundation (DFG), No. 445757098 and No. SFB 1039 Z01.
Institutional animal care and use committee statement: All experiments were conducted in accordance with the animal welfare guidelines and approved by the Regierungspräsidium Darmstadt, which is the responsible authority for animal studies in the federal state of Hessen, Germany (permit number FK/2003).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data supporting the findings of this study are included within the article and its
Supplementary material.
Corresponding author: Angela Brieger, PhD, Senior Scientist, Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Theodor-Stern-Kai 7, Frankfurt 60590, Hesse, Germany.
a.brieger@em.uni-frankfurt.de
Received: January 29, 2026
Revised: February 27, 2026
Accepted: April 16, 2026
Published online: August 14, 2026
Processing time: 175 Days and 17.6 Hours
BACKGROUND
Enhanced intestinal epithelial permeability contributes to disease progression in advanced liver disease. Patients with acute-on-chronic liver failure (ACLF) frequently exhibit gut barrier dysfunction. However, mechanisms underlying the transition from cirrhosis to ACLF remain incompletely understood. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of epithelial homeostasis, yet its role in intestinal barrier integrity during ACLF has not been explored.
AIM
To investigate whether imbalanced intestinal STAT3 expression drives gut barrier dysfunction during liver disease advancement, particularly during progression to ACLF, we analyzed its effects on tight junction architecture, lipid composition, and epithelial morphology.
METHODS
Morphology of intestinal tissues from mouse models of steatosis, cirrhosis, and ACLF was analyzed by hematoxylin and eosin staining while STAT3 expression and activation were determined by immunohistochemistry. Messenger RNA levels of Stat3, Stat1, and tight junction components [zonula occludens-1 (Tjp1), occludin (Ocln), claudin (Cldn) 1, Cldn2, and Cldn3] from intestinal mouse tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Additionally, stably differential STAT3-expressing epithelial Caco-2 or T84 monolayers were generated to assess barrier integrity using transepithelial electrical resistance measurements. Protein expression of STAT3, STAT1, zonula occludens-1, OCLN, claudin (CLDN) 1, CLDN2, and CLDN3 was determined by western blotting. Lipid composition was analyzed by lipidomics, and epithelial morphology was assessed through immunofluorescence and electron microscopy.
RESULTS
Liver disease progression was associated with pronounced intestinal morphological alterations accompanied by a marked increase in STAT3 expression during the transition from cirrhosis to ACLF. In vitro, elevated STAT3 levels induced tight junction remodeling, increased epithelial permeability, and significantly altered lipid composition. Lipidomic profiling revealed remodeling of major phospholipid, ether lipid, sphingolipid, lysophospholipid, and triglyceride classes, indicating disturbed epithelial membrane lipid homeostasis. These effects were paralleled by pronounced STAT3-dependent structural changes in epithelial monolayers.
CONCLUSION
Accumulation of unphosphorylated STAT3 may serve as a potential biomarker of gut barrier destabilization during the transition from cirrhosis to ACLF.
Core Tip: Intestinal barrier disfunction is frequently observed in acute-on-chronic liver failure (ACLF) secondary to chronic liver disease, yet the underlying molecular mechanisms remain largely unknown. This study identifies a disrupted expression pattern of the intestinal signal transducer and activator of transcription 3 (STAT3) as a central regulator of epithelial barrier integrity during the course of liver disease. Dysregulated STAT3 significantly impairs tight junction architecture and epithelial morphology, leading to increased intestinal permeability. The accumulation of unphosphorylated STAT3, independent of canonical STAT3 phosphorylation, may represent a potential biomarker linking cirrhosis to ACLF and could serve as a novel therapeutic target.
