ZD-4009, a novel B-cell lymphoma 9 inhibitor, is associated with ameliorated pulmonary fibrosis and reduced hypoxia-inducible factor 1α-mediated glycolysis and transforming growth factor-β/SMAD signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options, highlighting the need for new molecular targets and effective antifibrotic agents. In this study, we investigated the role of B-cell lymphoma 9 (BCL9) in IPF and evaluated the antifibrotic potential of ZD-4009, a novel small-molecule inhibitor targeting BCL9. BCL9 was upregulated in fibrotic lung tissues, suggesting a possible association between BCL9 and pulmonary fibrosis progression. ZD-4009 showed high-affinity binding to β-catenin (pKD = 7.36 ± 0.01, KD = 44.72 nM). In vitro, ZD-4009 inhibited fibroblast activation, suppressed extracellular matrix deposition, and reduced the expression of fibrosis-associated markers, including collagen type I alpha 1 chain (COL1A1) and alpha-smooth muscle actin (α-SMA). Mechanistically, ZD-4009 suppressed hypoxia-inducible factor 1α-associated glycolytic reprogramming and inhibited transforming growth factor-β (TGF-β)/SMAD family member (SMAD) signaling, suggesting that its antifibrotic effects are associated with coordinated regulation of metabolic and profibrotic pathways. In vivo, ZD-4009 treatment was associated with alleviated bleomycin (BLM)-induced pulmonary fibrosis, as reflected by improved survival from 55% in the BLM group to 82% in the BLM + ZD-4009 group, reduced relative collagen content from 61% to 48%, and ameliorated micro-computed tomography-assessed fibrotic changes. In the tested model, ZD-4009 showed favorable antifibrotic effects compared with nintedanib, whereas liposome-encapsulated ZD-4009 reduced treatment-related toxicity. Together, these findings nominate ZD-4009 as a promising antifibrotic candidate and highlight BCL9 as a potential therapeutic target for IPF. SIGNIFICANCE STATEMENT: ZD-4009 is a potent and selective B-cell lymphoma 9 inhibitor that suppresses fibroblast proliferation and extracellular matrix deposition in idiopathic pulmonary fibrosis. It shows superior antifibrotic efficacy compared with current therapies, positioning ZD-4009 as a promising therapeutic candidate for treating this progressive and untreatable disease.