JCI Insight. 2022 Aug 22;7(16):e160688. doi: 10.1172/jci.insight.160688.
There is a paucity of information about potential molecular brakes on the activation of fibroblasts that drive tissue fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) is best known as a determinant of cell stemness and a tumor suppressor. We found that its expression was diminished in fibroblasts from fibrotic lung. Gain- and loss-of-function studies showed that KLF4 inhibited fibroblast proliferation, collagen synthesis, and differentiation to myofibroblasts, while restoring their sensitivity to apoptosis. Conditional deletion of KLF4 from fibroblasts potentiated the peak degree of pulmonary fibrosis and abrogated the subsequent spontaneous resolution in a model of transient fibrosis. A small molecule inducer of KLF4 was able to restore its expression in fibrotic fibroblasts and elicit resolution in an experimental model characterized by more clinically relevant persistent pulmonary fibrosis. These data identify KLF4 as a pivotal brake on fibroblast activation whose induction represents a therapeutic approach in fibrosis of the lung and perhaps other organs.
关于潜在的分子制动器的信息很少，这些制动器可以阻止成纤维细胞的激活，从而导致组织纤维化。转录因子 Krüppel 样因子 4（KLF4）是众所周知的细胞干性决定因素和肿瘤抑制因子。我们发现，它在纤维化肺成纤维细胞中的表达减少。增益和失能研究表明，KLF4 抑制成纤维细胞增殖、胶原合成和向肌成纤维细胞分化，同时恢复其对细胞凋亡的敏感性。成纤维细胞中 KLF4 的条件性缺失增强了肺纤维化的峰值程度，并消除了瞬时纤维化模型中随后的自发缓解。KLF4 的小分子诱导剂能够恢复其在纤维化成纤维细胞中的表达，并在以更具临床相关性的持续性肺纤维化为特征的实验模型中引发缓解。这些数据表明 KLF4 是成纤维细胞激活的关键制动器，其诱导代表了治疗肺部和其他器官纤维化的一种方法。
