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ResearchIn-Press PreviewGastroenterologyHepatology Open Access | 10.1172/JCI206235

Nuclear prohibitin 1 depletion drives alcohol-associated liver injury and sensitization to colon cancer liver metastasis

Jyoti Chhimwal,1 Sonal Sinha,1 Jina Kim,2 Mario Alba,1 Lucía Barbier-Torres,1 Jiaohong Wang,1 Heping Yang,1 Youngyi Lim,1 Ramachandran Murali,3 Maria Lauda Tomasi,1 Sungyong You,2 José M. Mato,4 and Shelly C. Lu1

1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

Find articles by You, S. in: PubMed | Google Scholar |

1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, United States of America

2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States of America

3Research Division of Immunology, Department of Medicine and Biomedical Scie, Cedars-Sinai Medical Center, Los Angeles, United States of America

4CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia,, Spain

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Published October 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI206235.
Copyright © 2026, Chhimwal et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 6, 2026 - Version history
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Abstract

Alcohol-associated liver disease (ALD) is associated with higher incidence of colorectal liver metastasis (CRLM); prohibitin 1 (PHB1) defends against CRLM yet its role in ALD and ALD-CRLM is poorly understood and was investigated here. In human, murine, and in vitro ALD models, cytosolic and nuclear PHB1 were depleted, whereas mitochondrial PHB1 was preserved despite a loss in mitochondrial mass. Nuclear PHB1 loss was driven by CRM1-mediated export, and blocking this interaction with a PHB1 nuclear export signal (NES) peptide retained nuclear PHB1, ameliorating both ALD and ALD-CRLM. PHB1 NES prevented depletion of nuclear methionine adenosyltransferase α1, oxidative stress, and induction of matrix metalloproteinase 7 (MMP-7) and multiple oncogenes. Single-nucleus RNA sequencing of NIAAA diet-fed mouse livers and spatial transcriptomics of ALD-CRLM mice livers revealed that PHB1 NES treatment mitigated alcohol-induced metabolic and oncogenic stress, attenuated pro-inflammation and pro-fibrogenic responses, remodeled immunosuppressive microenvironment and contributed to overall hepatoprotection. These findings identify nuclear PHB1 depletion as a driver and a promising therapeutic target in ALD and ALD-CRLM.

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Version history
  • Version 1 (October 6, 2026): In-Press Preview
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