ArticleJournal of biomedical science2026
MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM/AMPK/FoxO1 pathway.
Article in Journal of biomedical science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPersistent injury and impaired regeneration of the alveolar epithelium are key contributors to the pathogenesis of pulmonary fibrosis. 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.
methodsThe effects of MPT0E028 on pulmonary fibrosis were assessed by evaluating the expression of fibrogenic proteins and cell markers of AT1 (T1α 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 T1α expression was examined in murine AT2 cells (MLE-12 cells).
resultsAdministration of MPT0E028 significantly reduced fibrosis scores; suppressed the expression of connective tissue growth factor, collagen I, fibronectin, and α-smooth muscle actin; and improved lung function in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 enhanced the expression of T1α 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 T1α 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 T1α expression, whereas transfection with FoxO3 siRNA had no effect. FoxO1 siRNA transfection also inhibited MPT0E028-stimulated T1α-luciferase activity. MPT0E028 induced FoxO1 serine phosphorylation, increased FoxO1 recruitment to the T1α promoter, and enhanced FoxO1-luciferase activity. Compound C, an AMPK inhibitor, and AMPK siRNA transfection suppressed MPT0E028-stimulated T1α expression, and compound C also inhibited MPT0E028-promoted FoxO1 recruitment to the T1α 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 T1α expression, AMPK and FoxO1 serine phosphorylation, FoxO1 recruitment to the T1α promoter, and FoxO1-luciferase activity. MPT0E028 induced FoxO1 phosphorylation in AT2 cells in the therapeutic model of BLM-induced pulmonary fibrosis in mice.
conclusionsMPT0E028 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.
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