School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China.
Theranostics. 2023 May 8;13(9):2787-2799. doi: 10.7150/thno.81993. eCollection 2023.
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.
特发性肺纤维化（IPF）是一种病因不明的进行性和致命性肺部疾病，目前尚无治愈方法。更好地了解疾病过程并确定可用药的靶点将有助于开发治疗 IPF 的有效疗法。我们之前曾报道 MDM4 通过 MDM4-p53 依赖性途径促进肺纤维化。然而，尚不清楚靶向该途径是否具有任何治疗潜力。在这项研究中，我们评估了 MDM4 的小分子抑制剂 XI-011 治疗肺纤维化的疗效。我们发现 XI-011 可显著降低原代人肌成纤维细胞和小鼠纤维化模型中 MDM4 的表达，并增加总 p53 和乙酰化 p53 的表达。XI-011 治疗可导致小鼠肺纤维化消退，而对正常成纤维细胞死亡或健康肺的形态无明显影响。基于这些发现，我们提出 XI-011 可能是治疗肺纤维化的一种有前途的治疗药物候选物。
