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Sanglifehrin A mitigates multiorgan fibrosis by targeting the collagen chaperone cyclophilin B.
- Source :
-
JCI insight [JCI Insight] 2024 Jun 20; Vol. 9 (15). Date of Electronic Publication: 2024 Jun 20. - Publication Year :
- 2024
-
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.
- Subjects :
- Animals
Humans
Mice
Collagen Type I metabolism
Fibrosis
Myofibroblasts metabolism
Myofibroblasts drug effects
Myofibroblasts pathology
Fibroblasts metabolism
Fibroblasts drug effects
Idiopathic Pulmonary Fibrosis drug therapy
Idiopathic Pulmonary Fibrosis pathology
Idiopathic Pulmonary Fibrosis metabolism
Lung pathology
Lung drug effects
Lung metabolism
Disease Models, Animal
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum drug effects
Male
Mice, Inbred C57BL
Transforming Growth Factor beta1 metabolism
Lactones
Spiro Compounds
Cyclophilins metabolism
Cyclophilins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 9
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 38900587
- Full Text :
- https://doi.org/10.1172/jci.insight.171162