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This study identified granulocyte colony-stimulating factor 3 (CSF3) as a key mediator of IPF progression. Elevated CSF3 expression was observed in the lung tissues of IPF patients. Recombinant CSF3 promoted myofibrogenesis in lung fibroblasts, whereas CSF3-deficient mice were protected from bleomycin-induced pulmonary fibrosis. Treatment with novel CSF3-neutralizing antibodies significantly restored fibrosis in IPF mice by suppressing myofibroblast differentiation and reducing ECM deposition. Here, we demonstrated a reciprocal regulatory relationship between CSF3 and TGF-\u03b2 that amplifies pro-fibrotic signaling. Our mechanistic studies revealed that CSF3 acts as an upstream regulator of TGF-\u03b2, forming a positive feedback loop that significantly accelerates the fibrotic process. Knockout or neutralization of CSF3 suppressed fibrosis by reducing TGF-\u03b2 levels, whereas treatment with recombinant CSF3 promoted fibrosis with increased TGF-\u03b2 expression. Notably, while CSF3 inhibition reduced TGF-\u03b2 expression levels, it did not decrease them below normal levels. This finding suggests that inhibiting CSF3 could simultaneously reduce fibrosis by suppressing excessive TGF-\u03b2 expression while also minimizing side effects by maintaining TGF-\u03b2 homeostasis. Taken together, these results provide strong evidence that CSF3 is a critical driver of IPF pathogenesis and that targeting CSF3 may provide a therapeutic strategy by modulating TGF-\u03b2 signaling and restoring the ECM and cellular homeostasis.<\/jats:p>","DOI":"10.1038\/s41392-025-02421-6","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T23:03:44Z","timestamp":1759359824000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Colony-stimulating factor 3 as a key mediator in the progression of idiopathic pulmonary fibrosis: a novel therapeutic target"],"prefix":"10.1038","volume":"10","author":[{"given":"Seungmo","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjoong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Sung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyeok","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Yeong","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eung-Suk","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Ji","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rae-kwon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8341-330X","authenticated-orcid":false,"given":"Joo Mi","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Sook","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Woo","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Woo","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Jung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Jae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"2421_CR1","first-page":"1","volume":"3","author":"FJ Martinez","year":"2017","unstructured":"Martinez, F. 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H.S.C. is a shareholder of FNCT Biotech. The company has a commercial interest in the development of CSF3-neutralizing antibodies discussed in this study. The authors declare that they are inventors on a patent application related to CSF3-neutralizing antibodies for treating pulmonary fibrosis, which is owned by FNCT Biotech. However, the experiments and analyses presented in this paper were conducted independently, and data integrity was rigorously maintained throughout the research process. The other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"322"}}