{"doi":"10.1101/2023.03.09.531890","title":"Sanglifehrin A mitigates multi-organ fibrosis in vivo by inducing secretion of the collagen chaperone cyclophilin B","abstract":"Abstract Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis by myofibroblasts have clinical potential as anti-fibrotic agents. Lysine hydroxylation by the prolyl-3-hydroxylase complex, comprised of cartilage associated protein, prolyl 3-hydroxylase 1, and cyclophilin B, is essential for collagen type I crosslinking and formation of stable fibers. Here, we identify the collagen chaperone cyclophilin B as a major cellular target of the macrocyclic natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Our studies reveal a unique mechanism of action in which SfA binding to cyclophilin B in the endoplasmic reticulum (ER) induces the secretion of cyclophilin B to the extracellular space, preventing TGF-β1–activated myofibroblasts from synthesizing collagen type I in vitro without inhibiting collagen type I mRNA transcription or inducing ER stress. In addition, SfA prevents collagen type I secretion without affecting myofibroblast contractility or TGF-β1 signaling. In vivo, we provide chemical, molecular, functional, and translational evidence that SfA mitigates the development of lung and skin fibrosis in mouse models by inducing cyclophilin B secretion, thereby inhibiting collagen synthesis from fibrotic fibroblasts in vivo . Consistent with these findings in preclinical models, SfA reduces collagen type I secretion from fibrotic human lung fibroblasts and precision cut lung slices from patients with idiopathic pulmonary fibrosis, a fatal fibrotic lung disease with limited therapeutic options. Our results identify the primary liganded target of SfA in cells, the collagen chaperone cyclophilin B, as a new mechanistic target for the treatment of organ fibrosis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394283,"datarank":0.24300025052630694,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.035056096358323324,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.035056096358323324,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":3,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1168610,"name":"Maria-Anna Chrysovergi","orcid":"0009-0007-4139-4666","position":1,"is_corresponding":false},{"id":501063,"name":"Hongwei Han","orcid":"0000-0002-0190-4461","position":2,"is_corresponding":false},{"id":995933,"name":"Farah Kabir","orcid":null,"position":3,"is_corresponding":false},{"id":1168920,"name":"Rachael T. Lister","orcid":null,"position":4,"is_corresponding":false},{"id":1168921,"name":"Chia‐Fu Chang","orcid":null,"position":5,"is_corresponding":false},{"id":303536,"name":"Katharine E. Black","orcid":null,"position":6,"is_corresponding":false},{"id":11000,"name":"David Lagares","orcid":"0000-0002-7317-8796","position":7,"is_corresponding":false},{"id":496356,"name":"Christina M. Woo","orcid":"0000-0001-8687-9105","position":8,"is_corresponding":false},{"id":843456,"name":"Hope A. Flaxman","orcid":"0000-0001-9717-7301","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:10.334330Z","pmid":"36945535","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}