Pharmacological inhibition of MDM4 alleviates pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology with no cure. A better understanding of the disease processes and identification of druggable targets will benefit the development of effective therapies for IPF. We previously reported that MDM4 promoted lung fibrosis through the MDM4-p53-dependent pathway. However, it remained unclear whether targeting this pathway would have any therapeutic potential. In this study, we evaluated the efficacy of XI-011, a small molecular inhibitor of MDM4, for treating lung fibrosis. We found that XI-011 significantly reduced MDM4 expression and increased the expression of total and acetylated p53 in primary human myofibroblasts and a murine fibrotic model. XI-011 treatment resulted in the resolution of lung fibrosis in mice with no notable impact on normal fibroblast death or the morphology of healthy lungs. Based on these findings, we propose that XI-011 might be a promising therapeutic drug candidate for treating pulmonary fibrosis.

• Authors: Qianru Mei, Zhenhua Yang, Zhengkai Xiang, He Zuo, Zijing Zhou, Xiaochuan Dong, Ludan Zhang, Wenhui Song, Yi Wang, Qinghua Hu, Yong Zhou, Jing Qu
• Journal: Theranostics (Theranostics) Vol. 13 Issue 9 Pg. 2787-2799 ( 2023) ISSN: 1838-7640 [Electronic] Australia
• PMID: 37284444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• (10-methyl-9-anthryl)methyl imidothiocarbamate
• Tumor Suppressor Protein p53
• Anthracenes
• MDM4 protein, human
• Proto-Oncogene Proteins
• Cell Cycle Proteins

Topics

• Humans
• Mice
• Animals
• Tumor Suppressor Protein p53 (metabolism)
• Idiopathic Pulmonary Fibrosis (drug therapy, metabolism)
• Anthracenes (pharmacology)
• Lung (metabolism)
• Fibroblasts (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Cell Cycle Proteins (metabolism)