{"doi":"10.1016/j.jbc.2023.105530","title":"A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis","abstract":"Fibroblast to myofibroblast transdifferentiation mediates numerous fibrotic disorders, such as idiopathic pulmonary fibrosis (IPF). We have previously demonstrated that non-muscle myosin II (NMII) is activated in response to fibrotic lung extracellular matrix, thereby mediating myofibroblast transdifferentiation. NMII-A is known to interact with the calcium-binding protein S100A4, but the mechanism by which S100A4 regulates fibrotic disorders is unclear. In this study, we show that fibroblast S100A4 is a calcium-dependent, mechanoeffector protein that is uniquely sensitive to pathophysiologic-range lung stiffness (8-25 kPa) and thereby mediates myofibroblast transdifferentiation. Re-expression of endogenous fibroblast S100A4 rescues the myofibroblastic phenotype in S100A4 KO fibroblasts. Analysis of NMII-A/actin dynamics reveals that S100A4 mediates the unraveling and redistribution of peripheral actomyosin to a central location, resulting in a contractile myofibroblast. Furthermore, S100A4 loss protects against murine in vivo pulmonary fibrosis, and S100A4 expression is dysregulated in IPF. Our data reveal a novel mechanosensor/effector role for endogenous fibroblast S100A4 in inducing cytoskeletal redistribution in fibrotic disorders such as IPF.","journal":"Journal of Biological Chemistry","year":2023,"id":328193,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"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":995140,"name":"Haiyan Li","orcid":"0000-0002-5541-3035","position":1,"is_corresponding":false},{"id":1050140,"name":"Hongxia Mao","orcid":null,"position":2,"is_corresponding":false},{"id":302608,"name":"James F. Crish","orcid":"0000-0002-3525-679X","position":3,"is_corresponding":false},{"id":303542,"name":"L. Grove","orcid":null,"position":4,"is_corresponding":false},{"id":302606,"name":"R.G. Scheraga","orcid":"0000-0001-5113-543X","position":5,"is_corresponding":false},{"id":1050141,"name":"Sanaa Mansoor","orcid":null,"position":6,"is_corresponding":false},{"id":1050142,"name":"A. Reinhardt","orcid":null,"position":7,"is_corresponding":false},{"id":303541,"name":"Susamma Abraham","orcid":null,"position":8,"is_corresponding":false},{"id":427968,"name":"Gauravi Deshpande","orcid":"0000-0002-1621-1553","position":9,"is_corresponding":false},{"id":1050143,"name":"Alicia Loui","orcid":null,"position":10,"is_corresponding":false},{"id":337145,"name":"Andrei I. Ivanov","orcid":"0000-0003-4823-209X","position":11,"is_corresponding":false},{"id":326792,"name":"Steven S. Rosenfeld","orcid":"0000-0003-1909-7116","position":12,"is_corresponding":false},{"id":710174,"name":"Anne R. Bresnick","orcid":"0000-0003-1674-4568","position":13,"is_corresponding":false},{"id":278243,"name":"Mitchell A. Olman","orcid":"0000-0003-3262-3598","position":14,"is_corresponding":false},{"id":302607,"name":"Brian D. Southern","orcid":"0000-0003-2983-5741","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-07-19T01:08:52.196069Z","pmid":"38072048","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":[]}