1. School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
2. Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China.
3. Department of Pulmonary and Critical Care Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
4. Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
5. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, the University of Alabama at Birmingham, Birmingham, AL, United States.
# Equal contribution
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.
Keywords: Idiopathic pulmonary fibrosis, MDM4-p53 pathway, MDM4 inhibitor, XI-011, Therapeutic drug.