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In idiopathic pulmonary fibrosis (IPF), type 2 alveolar epithelial (AT2) cells fail to fully differentiate into type 1 alveolar epithelial (AT1) cells, remaining instead in a transitional state. Histone deacetylase (HDAC) inhibitors are promising therapeutic agents for pulmonary fibrosis. Therefore, this study investigated whether MPT0E028, a pan-HDAC inhibitor, ameliorated bleomycin (BLM)-induced pulmonary fibrosis in a therapeutic model of mice by promoting AT2-to-AT1 cell differentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of MPT0E028 on pulmonary fibrosis were assessed by evaluating the expression of fibrogenic proteins and cell markers of AT1 (T1\u03b1 and aquaporin 5 [AQP5]), AT2 (surfactant protein C [SPC]) and alveolar epithelial transitional cells (Keratin 8 [KRT8]) in a therapeutic model of BLM-induced pulmonary fibrosis in mice. The role of the ataxia-telangiectasia mutated (ATM)\/AMP-activated protein kinase (AMPK)\/forkhead box O1 (FoxO1) signaling pathway in MPT0E028-induced T1\u03b1 expression was examined in murine AT2 cells (MLE-12 cells).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Administration of MPT0E028 significantly reduced fibrosis scores; suppressed the expression of connective tissue growth factor, collagen I, fibronectin, and \u03b1-smooth muscle actin; and improved lung function in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 enhanced the expression of T1\u03b1 and AQP5 but reduced the expression of SPC and KRT8 in lung tissues from BLM-treated mice. In MLE-12 cells and primary human AT2 cells, MPT0E028 upregulated T1\u03b1 and AQP5 expression in a time-dependent manner, with this accompanied by a decrease in SPC expression. AS1842856, an FoxO1 inhibitor, and FoxO1 siRNA transfection inhibited MPT0E028-stimulated T1\u03b1 expression, whereas transfection with FoxO3 siRNA had no effect. FoxO1 siRNA transfection also inhibited MPT0E028-stimulated T1\u03b1-luciferase activity. MPT0E028 induced FoxO1 serine phosphorylation, increased FoxO1 recruitment to the T1\u03b1 promoter, and enhanced FoxO1-luciferase activity. Compound C, an AMPK inhibitor, and AMPK siRNA transfection suppressed MPT0E028-stimulated T1\u03b1 expression, and compound C also inhibited MPT0E028-promoted FoxO1 recruitment to the T1\u03b1 promoter. MPT0E028 induced AMPK phosphorylation in a time-dependent manner and increased ATM acetylation and phosphorylation in MLE-12 cells. ATM siRNA transfection suppressed MPT0E028-induced T1\u03b1 expression, AMPK and FoxO1 serine phosphorylation, FoxO1 recruitment to the T1\u03b1 promoter, and FoxO1-luciferase activity. MPT0E028 induced FoxO1 phosphorylation in AT2 cells in the therapeutic model of BLM-induced pulmonary fibrosis in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MPT0E028 is the first pan-HDAC inhibitor shown to activate ATM acetylation-mediated AMPK\/FoxO1 signaling to induce AT2-to-AT1 differentiation in a therapeutic model of BLM-induced pulmonary fibrosis in mice. Administration of MPT0E028 after BLM challenge effectively ameliorated pulmonary fibrosis by suppressing fibrogenic protein expression and promoting AT2-to-AT1 cell differentiation. These results suggest that MPT0E028 holds potential as a therapeutic agent for IPF treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01281-8","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:58:35Z","timestamp":1784642315000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM\/AMPK\/FoxO1 pathway"],"prefix":"10.1186","volume":"33","author":[{"given":"Chia-Hao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Sheng","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Ping","family":"Liou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wun-Hao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Sheng","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Chang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Huang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"1281_CR1","doi-asserted-by":"publisher","first-page":"802989","DOI":"10.3389\/fmed.2021.802989","volume":"8","author":"V Cottin","year":"2021","unstructured":"Cottin V, Spagnolo P, Bonniaud P, Nolin M, Dalon F, Kirchg\u00e4ssler KU, et al. 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