ResearchIn-Press PreviewInflammationTherapeutics
Open Access | 10.1172/jci.insight.171162
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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Chrysovergi, M.
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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Weigert, A.
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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Savai, R.
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
Find articles by Pardo-Saganta, A. in: JCI | PubMed | Google Scholar
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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Lagares, D.
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1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States of America
2Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
3Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
4Molecular Mechanisms in Lung Cancer, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
5Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
6Lung Inflammation and Repair, Institute for Lung Health, Giessen, Germany
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Published June 20, 2024 - More info
Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis have potential as anti-fibrotic agents. We identify the collagen chaperone cyclophilin B as a major cellular target of the natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Mechanistically, SfA inhibits and induces the secretion of cyclophilin B from the endoplasmic reticulum (ER) and prevents TGF-β1–activated myofibroblasts from synthesizing and secreting collagen type I in vitro, without inducing ER stress, affecting collagen type I mRNA transcription, myofibroblast migration, contractility, or TGF-β1 signaling. In vivo, SfA induced cyclophilin B secretion in preclinical models of fibrosis, thereby inhibiting collagen synthesis from fibrotic fibroblasts and mitigating the development of lung and skin fibrosis in mice. Ex vivo, SfA induces cyclophilin B secretion and inhibits collagen type I secretion from fibrotic human lung fibroblasts and samples from patients with idiopathic pulmonary fibrosis (IPF). Taken together, we provide chemical, molecular, functional, and translational evidence for demonstrating direct anti-fibrotic activities of SfA in preclinical and human ex vivo fibrotic models. Our results identify the cellular target of SfA, the collagen chaperone cyclophilin B, as a mechanistic target for the treatment of organ fibrosis.