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

• DOI: 10.1172/jci.insight.171162
• Publication Date: 2024-06-20T16:00:55Z
• Authors: Hope A. Flaxman; Maria-Anna Chryso...; Hongwei Han; Farah Kabir; Rachael T. Lister; Chia-Fu Chang; Robert Yvon; Katharine E. Black; Andreas Weigert; Rajkumar Savai; Alejandro Egea-Zo...; Ana Pardo-Saganta; David Lagares; Christina M. Woo
• Keywords: Male; Fibroblasts; Endoplasmic Reticulum; Fibrosis; Collagen Type I; Idiopathic Pulmonary Fibrosis; Mice, Inbred C57BL; Transforming Growth Factor beta1; Mice; Cyclophilins; Disease Models, Animal; Lactones; Animals; Humans; Spiro Compounds; Myofibroblasts; Lung; Research Article

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.