ABSTRACT
Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available. In this study, we reported the enhanced expression of mesenchymal homobox 1 (MEOX1) in pulmonary fibrosis patients, especially in their fibroblasts and endothelial cells, and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes. By high-throughput screening, we identified Ailanthone (AIL) from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1. AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-ß1 (TGF-ß1). In an animal model of bleomycin-induced pulmonary fibrosis, AIL effectively mitigated the fibrotic process and restored respiratory functions. Mechanistically, AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1, thereby inhibiting MEOX1 expression and activity. In summary, our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis. Moreover, we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis, specifically through the suppression of JUN-dependent MEOX1 activation.