Pharmacological inhibition of MDM4 alleviates pulmonary fibrosis.

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致命性肺部疾病，无法治愈。更好地了解疾病进程并确定可成药靶点将有助于开发针对IPF的有效疗法。我们先前报道过，MDM4通过MDM4 - p53依赖途径促进肺纤维化。然而，针对该途径是否具有任何治疗潜力仍不清楚。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显著降低了原代人肌成纤维细胞和小鼠纤维化模型中MDM4的表达，并增加了总p53和乙酰化p53的表达。XI - 011治疗使小鼠的肺纤维化得到缓解，对正常成纤维细胞死亡或健康肺的形态没有显著影响。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景的候选治疗药物。