{"doi":"10.1172/jci174598","title":"A fibroblast-dependent TGF-β1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis","abstract":"Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-β1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-β1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-β1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-β1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-β1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-β1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-β1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.","journal":"Journal of Clinical Investigation","year":2024,"id":417416,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":70,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":841083,"name":"Alexis N. Brumwell","orcid":null,"position":1,"is_corresponding":false},{"id":1166565,"name":"Tsung Che Ho","orcid":null,"position":2,"is_corresponding":false},{"id":1203682,"name":"Kiana Garakani","orcid":null,"position":3,"is_corresponding":false},{"id":289737,"name":"Genevieve Montas","orcid":"0000-0003-3249-014X","position":4,"is_corresponding":false},{"id":289738,"name":"Darren Leong","orcid":"0000-0001-6959-153X","position":5,"is_corresponding":false},{"id":1079315,"name":"Vivianne W. Ding","orcid":null,"position":6,"is_corresponding":false},{"id":74580,"name":"Jeffrey A. Golden","orcid":"0000-0001-9933-5502","position":7,"is_corresponding":false},{"id":290572,"name":"Binh N. Trinh","orcid":null,"position":8,"is_corresponding":false},{"id":300085,"name":"David M. Jablons","orcid":null,"position":9,"is_corresponding":false},{"id":231443,"name":"Michael A. Matthay","orcid":"0000-0003-3039-8155","position":10,"is_corresponding":false},{"id":289740,"name":"Kirk D. Jones","orcid":"0000-0002-0275-3503","position":11,"is_corresponding":false},{"id":3386,"name":"Paul J. Wolters","orcid":"0000-0002-3108-6164","position":12,"is_corresponding":false},{"id":1166128,"name":"Ying Wei","orcid":"0000-0002-4247-1770","position":13,"is_corresponding":false},{"id":84713,"name":"Harold A. Chapman","orcid":"0000-0002-5280-5527","position":14,"is_corresponding":false},{"id":289739,"name":"Claude Jourdan Le Saux","orcid":"0000-0002-6041-2870","position":15,"is_corresponding":false},{"id":486357,"name":"Max Cohen","orcid":"0000-0001-6014-5816","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:56:50.743370Z","pmid":"38980870","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":[]}