Ailanthone ameliorates pulmonary fibrosis by suppressing JUN-dependent MEOX1 activation  

作　　者：Lixin Zhao Yuguang Zhu Hua Tao Xiying Chen Feng Yin Yingyi Zhang Jianfeng Qin Yongyin Huang Bikun Cai Yonghao Lin Jiaxiang Wu Yu Zhang Lu Liang Ao Shen Xi-Yong Yu 

机构地区：[1]The Fifth Affiliated Hospital,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology,NMPA&State Key Laboratory,School of Pharmaceutical Sciences,Guangzhou Medical University,Guangzhou 511436,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3543-3560,共18页药学学报（英文版）

基　　金：support from National Key R&D Program of China(2022YFE0209700);the National Natural Science Foundation of China(82070406,82000080,and 82304486);Guangdong Provincial Drug Administration Science and Technology Innovation Program(2023ZDZ05,2022ZDZ10,China);supported by a funding from the Department of Science and Technology of Guangdong to AS(2024A1515010574,China).

摘　　要：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-b1(TGF-b1).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.

关 键 词：Ailanthone MEOX1 Pulmonary fibrosis JUN TGF-B1 High-throughput screening Natural product 

分 类 号：R96[医药卫生—药理学]