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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-(31-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-(31 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.