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Publications

Journal Article Epublish 4 citations

PubMed: 38900587 DOI: 10.1172/jci.insight.171162

Sanglifehrin A mitigates multiorgan fibrosis by targeting the collagen chaperone cyclophilin B.

JCI Insight 9(15)

Authors: Hope A Flaxman, Maria-Anna Chrysovergi, Hongwei Han, Farah Kabir, Rachael T Lister, Chia-Fu Chang, Robert Yvon, Katharine E Black, Andreas Weigert, Rajkumar Savai, Alejandro Egea-Zorrilla, Ana Pardo-Saganta, David Lagares, Christina M Woo

Affiliations

  • Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
  • Fibrosis Research Center, Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Germany.
  • Frankfurt Cancer Institute (FCI), Goethe University, and German Cancer Consortium (DKTK), Germany.
  • Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
  • Institute for Lung Health (ILH), Department of Internal Medicine, Justus-Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), DZL, Giessen, Germany.
  • Cardio-Pulmonary Institute (CPI), Department of Internal Medicine, Justus Liebig University, Giessen, Germany.

Abstract

Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis have potential as antifibrotic agents. We identify the collagen chaperone cyclophilin B as a major cellular target of the natural product sanglifehrin A (SfA) using photoaffinity 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 or 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 antifibrotic 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.

MeSH

Lung, Myofibroblasts, Fibrosis, Biomedical Research, Collagen, Cyclophilins, Fibroblasts, Therapeutics, Collagen Type I

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