{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:53:30Z","timestamp":1785405210636,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K01 AR083019"],"award-info":[{"award-number":["K01 AR083019"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K24 AR060297"],"award-info":[{"award-number":["K24 AR060297"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"award":["K01 AR083019"],"award-info":[{"award-number":["K01 AR083019"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K24 AR060297"],"award-info":[{"award-number":["K24 AR060297"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]},{"name":"SmartState Center for Inflammation and Fibrosis Research at the Medical University of South Carolina"},{"id":[{"id":"https:\/\/ror.org\/012jban78","id-type":"ROR","asserted-by":"publisher"}]},{"name":"IPF Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Systemic sclerosis (SSc) is a systemic autoimmune disease leading to extensive fibrosis of the skin and many visceral organs, including the lungs. The need for effective treatments is urgent, as none exists today that can stop or reverse the progression of fibrosis. We examined the effect of restoring KLF4 levels in primary human lung fibroblasts of SSc patients with pulmonary fibrosis as a potential therapeutic strategy. Methods: We restored KLF4 levels in SSc lung fibroblasts by adenoviral infection and extracted total RNA for RNA sequencing. Genes and systems level analyses were performed, and selected genes of interest and markers of alveolar, inflammatory, and fibrotic fibroblasts were further validated at the mRNA and protein levels. Results: Our results showed that restoring KLF4 levels in SSc lung fibroblasts initiated dedifferentiation of \u03b1SMA and CTHRC1, expressing myofibroblasts by repressing markers of inflammatory and fibrotic fibroblasts while boosting markers of alveolar fibroblasts. Our data also revealed that restoring KLF4 levels prevented TGF\u03b21-induced fibrogenesis in normal lung fibroblasts, and reduced fibrosis in explanted human lungs in organ culture. Conclusions: Our results in human primary SSc lung fibroblasts showed that restoring KLF4 levels initiated dedifferentiation of fibrotic and inflammatory fibroblasts towards the phenotype of alveolar fibroblasts, their lineage precursors, highlighting the potential of KLF4 as a therapy to stop and reverse fibrosis.<\/jats:p>","DOI":"10.3390\/cells15100921","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["KLF4 Initiates Dedifferentiation of Systemic Sclerosis Lung Fibroblasts"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9300-5032","authenticated-orcid":false,"given":"Ludivine","family":"Renaud","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Kotz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0211-4509","authenticated-orcid":false,"given":"Aravind","family":"Menon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 816, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-6407","authenticated-orcid":false,"given":"Carol","family":"Feghali-Bostwick","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/ard.2006.066068","article-title":"Changes in causes of death in systemic sclerosis, 1972\u20132002","volume":"66","author":"Steen","year":"2007","journal-title":"Ann. 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