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Depression and anxiety are common comorbidities in patients with IPF, and emerging evidence suggests that neuroactive pathways may also influence fibrotic remodeling. On this basis, we investigated desipramine, a tricyclic antidepressant, as a potential modulator of fibroblast state in lung fibrosis. Desipramine was identified in an FDA-approved compound screen as a pro-lipogenic hit in TGF-\u03b2-stimulated fibroblasts and was subsequently evaluated across a stepwise validation pipeline of increasing biological complexity. In WI-38 fibroblasts, desipramine was well tolerated at 10 \u03bcM and reduced myofibroblast-associated features while increasing lipid-associated staining. In a fibroblast-supported alveolosphere assay, desipramine altered qualitative organoid clustering and changed the transcript levels of specific mesenchymal markers under profibrotic stimulation, whereas direct treatment of MLE-12 epithelial cells did not elicit a consistent response. While desipramine demonstrated pro-lipogenic and anti-myofibroblastic phenotypic shifts in reductionist 2D cultures, these effects failed to translate robustly into complex 3D human lung tissue slices or in vivo disease models. Ultimately, our findings highlight the critical necessity of utilizing complex translational pipelines to rigorously validate early screening hits before therapeutic efficacy is assumed.<\/jats:p>","DOI":"10.3390\/cells15151344","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stepwise Translational Validation of the Screening Hit Desipramine Reveals Limits of Fibroblast-State Modulation in Lung Fibrosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3578-6344","authenticated-orcid":false,"given":"Georgios-Dimitrios","family":"Panagiotidis","sequence":"first","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"},{"name":"Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany"},{"name":"Institute for Lung Health (ILH), 35392 Giessen, Germany"},{"name":"Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-4945","authenticated-orcid":false,"given":"Stefano","family":"Rivetti","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"},{"name":"Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany"},{"name":"Institute for Lung Health (ILH), 35392 Giessen, Germany"},{"name":"Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5015-4280","authenticated-orcid":false,"given":"Manuela","family":"Marega","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"},{"name":"Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany"},{"name":"Institute for Lung Health (ILH), 35392 Giessen, Germany"},{"name":"Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Noori","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"},{"name":"Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany"},{"name":"Institute for Lung Health (ILH), 35392 Giessen, Germany"},{"name":"Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3417","authenticated-orcid":false,"given":"Elie","family":"El Agha","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany"},{"name":"Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany"},{"name":"Institute for Lung Health (ILH), 35392 Giessen, Germany"},{"name":"Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, 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