Zhong Wen-Jing, Zhang Chen-Yu, Duan Jia-Xi, Chen Meng-Rui, Zhang Bo-Liang, Yang Nan-Shi-Yu, Sha Han-Xi, Zhang Jun, Xiong Jian-Bing, Guan Cha-Xiang, Zhou Yong
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of the General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, Hunan 410078, China; National Experimental Teaching Demonstration Center for Medical Function, Changsha, Hunan 410078, China.
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
Int J Biol Macromol. 2024 Sep 11;280(Pt 1):135351. doi: 10.1016/j.ijbiomac.2024.135351.
Pulmonary fibrosis (PF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia, occurring primarily in older adults with poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. However, the molecular mechanisms regulating AEC senescence in PF are incompletely understood. Herein, we provided evidence to support the function of Krüppel-like factor 14 (KLF14), a novel Krüppel-like transcription factor, in the regulation of AEC senescence during PF. We confirmed that the expression of KLF14 was up-regulated in PF patients and mice treated with bleomycin (BLM). KLF14 knockdown resulted in more pronounced structural disruption of the lung tissue and swelling of the alveolar septum, which led to significantly increased mortality in BLM-induced PF mice. Mechanistically, RNA-seq analysis indicated that KLF14 decreased the senescence of AECs by inhibiting endoplasmic reticulum (ER) stress. Furthermore, the pharmacological activation of KLF14 conferred protection against PF in mice. In conclusion, our findings reveal a protective role for KLF14 in preventing AECs from senescence and shed light on the development of KLF14-targeted therapeutics for PF.
肺纤维化（PF）被定义为一种慢性、进行性纤维化间质性肺炎的特定形式，主要发生于预后较差的老年人。肺泡上皮细胞（AEC）衰老为PF的关键病理机制。然而，PF中调节AEC衰老的分子机制尚未完全明确。在此，我们提供证据支持一种新型Krüppel样转录因子Krüppel样因子14（KLF14）在PF期间调节AEC衰老中的作用。我们证实，PF患者以及用博来霉素（BLM）处理的小鼠中KLF14的表达上调。敲低KLF14导致肺组织结构破坏更明显以及肺泡间隔增宽，这导致BLM诱导的PF小鼠死亡率显著增加。从机制上来说，RNA测序分析表明KLF14通过抑制内质网（ER）应激降低AEC衰老。此外，KLF14的药理学激活赋予小鼠抗PF保护作用。总之，我们的研究结果揭示了KLF14在防止AEC衰老中的保护作用，并为开发针对PF的KLF14靶向疗法提供了思路。
