Evidence map›Paper›PMID 41654223›Full record

ArticleJournal of hepatology2026

Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease.

Marcos F Fondevila, Henriette Kreimeyer, Cynthia L Hsu, Joaquin Tamargo-Azpilicueta, Le Z Day, Marina Gritsenko, Kwame Attah, Noemí Cabré, Aenne Harberts, Fernanda Raya Tonetti and 21 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Faecal Cathepsin B and S Are Associated With Liver Disease Severity and Adiposity in MASLD.Liver international : official journal of the International Association for the Study of the Liver · 2026
    Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors.

Marcos F FondevilaDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Henriette KreimeyerDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Cynthia L HsuDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA.
Joaquin Tamargo-AzpilicuetaInstitute for Chemical Research (IIQ), Scientific Research Center Isla de la Cartuja (cicCartuja), University of Seville - CSIC, Seville, Spain.
Le Z DayBiological Sciences and Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Marina GritsenkoBiological Sciences and Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Kwame AttahBiological Sciences and Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Noemí CabréDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Aenne HarbertsDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany.
Fernanda Raya TonettiDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Yongqiang YangDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Tomoo YamazakiDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
David SchölerDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Alvaro EguileorDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Colleen BlasioDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Abraham S MeijnikmanDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
Xinlian ZhangDivision of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
Ricard Garcia-CarbonellDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, California, USA.
Vivian HookDepartment of Pharmacology, University of California San Diego, La Jolla, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA; Department of Neurosciences, University of California, La Jolla, California, USA.
Enchen ZhouDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
Zhaoli SunDepartment of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jon M JacobsBiological Sciences and Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
Jerrold R TurnerLaboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Cristina LlorenteDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
AlcHepNet Investigators
Christopher K GlassDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
Peter StärkelDepartment of Hepatology and Gastroenterology, St. Luc University Hospital, Catholic University of Louvain, Brussels, Belgium.
Thomas ReinheckelInstitute of Molecular Medicine and Cell Research, Medical Faculty and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Irene Diaz-MorenoInstitute for Chemical Research (IIQ), Scientific Research Center Isla de la Cartuja (cicCartuja), University of Seville - CSIC, Seville, Spain.
David J GonzalezDepartment of Pharmacology, University of California San Diego, La Jolla, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA.
Bernd SchnablDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA. Electronic address: beschnabl@ucsd.edu.

Funding

The Southernearch Center for ALPD and CirrhosisP50AA011999 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HIDEKAZU TSUKAMOTO · 1999 to 2026
$45.8M
ZO-1-MEDIATED PROTEIN INTERACTIONS: REGULATORS AND INTEGRATORS OF DIVERSE EPITHELIAL FUNCTIONS IN HEALTH AND DISEASER01DK061931 · NIDDK · UNIVERSITY OF CHICAGO · PI JERROLD R. TURNER · 2001 to 2026
$15.0M
San Diego Digestive Diseases Research CenterP30DK120515 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Bernd G. Schnabl · 2019 to 2026
$10.8M
The Role of the Intestinal Mycobiome in Alcoholic Liver DiseaseR01AA024726 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Bernd G. Schnabl · 2018 to 2026
$3.9M
Intestinal proteases in alcohol-associated liver diseaseR01AA031710 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SCHNABL, BERND G. · 2025 to 2025
$3.2M
Microbiome and Intestinal Innate Immune Response in Alcoholic Liver DiseaseR37AA020703 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Bernd G. Schnabl · 2021 to 2026
$2.5M
Role of gut microbial ethanol production in alcohol use disorder and alcohol-associated liver diseaseR00AA031328 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Cynthia Li-Shin Hsu · 2025 to 2026
$497k
Defining single-channel paracellular (tight junction) conductances using nanotechnologyR21GM144801 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI TURNER, JERROLD R. · 2023 to 2024
$469k
The role of intestinal gp130 in alcohol-associated liver diseaseR21AA030654 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LLORENTE IZQUIERDO, ANA CRISTINA · 2023 to 2023
$415k
BLRD VA I01 BX004594NIAAA NIH HHS P50 AA011999NIAAA NIH HHS R00 AA031328NIAAA NIH HHS R01 AA024726NIAAA NIH HHS R01 AA031710NIAAA NIH HHS R21 AA030654NIAAA NIH HHS R37 AA020703NIDDK NIH HHS P30 DK120515NIDDK NIH HHS R01 DK061931NIGMS NIH HHS R21 GM144801
6 · The paper itself

Abstract

BACKGROUND &

aimsDisruption of the intestinal barrier facilitates microbial translocation to the liver and contributes to chronic liver disease. We aimed to study the role of the fecal proteome in disease progression in patients with alcohol-associated hepatitis.

methodsWe used fecal proteomics data from a multicenter cohort of patients with alcohol-associated hepatitis (n = 80), alcohol use disorder (n = 20), and controls (n = 19) (InTeam), and a cathepsin B activity assay in an independent multicenter cohort of patients with alcohol-associated hepatitis (n = 80), alcohol use disorder (n = 20), and controls (n = 18) (AlcHepNet). Mice lacking cathepsin B in myeloid cells and transgenic mice overexpressing occludin in intestinal epithelial cells, were subjected to the chronic-plus-binge ethanol feeding model (NIAAA).

resultsFecal proteomics and activity analysis revealed that the protease cathepsin B progressively increased with alcohol use disorder and alcohol-associated hepatitis compared to controls, and is associated with higher short-term mortality in patients with alcohol-associated hepatitis. Cathepsin B is predominantly expressed in intestinal macrophages and is upregulated by ethanol. Cathepsin B deficiency in myeloid cells or oral treatment with the gut-restricted cathepsin B inhibitor CA074 stabilized the gut barrier by preserving the tight junction protein occludin, lowered serum lipopolysaccharide levels, and attenuated ethanol-induced steatohepatitis. Transgenic overexpression of occludin in intestinal epithelial cells sufficed to reduce steatohepatitis and blunted the effects of CA074 in ethanol-fed mice. Cathepsin B proteolytically cleaves occludin in enzymatic assays, and its inhibition prevented occludin degradation and barrier disruption in intestinal organoids and epithelial monolayers. Molecular modeling and peptide profiling reveal specific cathepsin B-induced cleavage sites in the extracellular region of occludin.

conclusionsIntestinal cathepsin B is an essential mediator of gut barrier dysfunction and a potential therapeutic target in alcohol-associated liver disease. IMPACT AND IMPLICATIONS: Intestinal barrier disruption facilitates microbial translocation to the liver, contributing to the progression of alcohol-associated liver disease; however, the molecular mechanisms driving barrier dysfunction remain incompletely understood. Our study identifies the protease cathepsin B as a key contributor to alcohol-associated liver disease progression by degrading the extracellular region of the tight junction protein occludin in the intestine, thereby leading to barrier disruption. This work advances the field by establishing causality, uncovering the molecular target, and proposing cathepsin B as a promising therapeutic target in alcohol-associated hepatitis - a condition for which liver transplantation remains the only effective treatment in a limited subset of patients.

Indexed as

Cathepsin BHepatitis, AlcoholicLiver Diseases, AlcoholicMacrophagesOccludinTight JunctionsAnimalsEthanolFecesFemaleHumansIntestinal Barrier FunctionIntestinal MucosaMaleMiceMice, TransgenicCathepsin BEthanolOccludinalcoholALDcathepsingut-liver axisintestinal barrierliver diseasemicrobiomeoccludinproteaseSLDtight junction

Identifiers

PMID41654223
PMCPMC13197211

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.