ArticleRespiratory research2025
An orally bioavailable BRD4 inhibitor disrupts expansion of a pathogenic epithelial-mesenchymal niche in bleomycin-induced fibrosis.
Article in Respiratory research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Article
- IRF1 mediates airway epithelial innate memory through priming BRD4- EP300 activity.Frontiers in immunology · 2026Article
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Authors and funding
11 authors.
Funding
Abstract
backgroundIdiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal disease with few effective therapies available. Fibrosis is driven, in part, by cell-state transitions of epithelial progenitors within the airways that repopulate the injured alveoli. This alveolar atypia affects gas exchange and stimulates ECM production. We sought to examine the role of BRD4 signaling in progenitor expansion in bleomycin-induced lung injury.
methodsActivation of the Bromodomain-containing protein 4 (BRD4) epigenetic regulator in distinct stem cell populations was quantitated in a high-resolution scRNA-seq time course of bleomycin-induced injury, and confirmed in scRNA-seq studies in human IPF. A potent, selective, and orally bioavailable BRD4 inhibitor (BRD4i, ZL0969) was rationally designed and synthesized. The effect of BRD4i on myofibroblast transition, progenitor cell expansion and fibrosis was evaluated using a therapeutic experimental design in C57BL6/mice.
resultsWe find that the BRD4 pathway is rapidly induced in regenerating activated alveolar type (AT)2 cells and persists in a population of pro-fibrotic Krt8 + progenitors expressing markers of epithelial mesenchymal transition as well as senescence. To test the functional role of BRD4 activation, we administered a potent, selective, and orally bioavailable BRD4 inhibitor (BRD4i, ZL0969) with ~ 80 nM IC
conclusionsThese data demonstrate that inhibition of BRD4 signaling prevents expansion of myofibroblasts and expansion of a pathogenic epithelial progenitor population controlling alveolar atypia and fibrosis.
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