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Conventional preclinical models, such as the bleomycin (BLM)-induced lung fibrosis (BILF) model in immunocompetent mice, fail to replicate the complexity of the human immune environment and are thus unsuitable for evaluating human-specific antibody and cell therapies. To overcome this limitation, we developed two humanized mouse models with functional human immune components: one engrafted with peripheral blood mononuclear cells (PBMCs) and the other with hematopoietic stem cells (HSCs). Pulmonary fibrosis was induced using BLM in both humanized models. In the PBMC-humanized model, human T cells accounted for 79.9%\u2009\u00b1\u20099.7% of CD45\n                    <jats:sup>+<\/jats:sup>\n                    cells; however, this model was limited by high incidence of graft-versus-host disease (GvHD). In contrast, the HSC-humanized model demonstrated stable multilineage engraftment (T cells: 20.1%\u2009\u00b1\u200928.3%; B cells: 56.8%\u2009\u00b1\u200925.4%), absence of GvHD, and consistent fibrotic pathology. Both models exhibited increased inflammatory infiltration, fibroblast activation, and collagen deposition following BLM induction. Nintedanib treatment significantly ameliorated fibrotic changes in both models. These findings establish the HSC-humanized BILF model as a clinically relevant platform for investigating human immune responses in IPF and for preclinical evaluation of human-targeted therapies.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-18370-7","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T11:49:41Z","timestamp":1759751381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Establishment of a humanized mouse model of pulmonary fibrosis for advancing drug validation strategies"],"prefix":"10.1038","volume":"15","author":[{"given":"Md. 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All animal experiments were performed in compliance with institutional guidelines and were approved by the Institutional Animal Care and Use Committee (IACUC) of Kyungpook National University (Approval No. KNU 2024\u20130536).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors consent to the publication of this work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"34748"}}