Krüppel-like transcription factor 14 alleviates alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress in pulmonaryfibrosis

Wen-Jing Zhong; Chen-Yu Zhang; Jia-Xi Duan; Meng-Rui Chen; Ping-Deng; Bo-Liang Zhang; Nan-Shi-Yu Yang; Han-Xi Sha; Jun Zhang; Jian-Bing Xiong; Cha-Xiang Guan; Yong Zhou

doi:10.1016/j.ijbiomac.2024.135351

Krüppel-like transcription factor 14 alleviates alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress in pulmonaryfibrosis

Int J Biol Macromol. 2024 Sep 11;280(Pt 1):135351. doi: 10.1016/j.ijbiomac.2024.135351. Online ahead of print.

Authors

Affiliations

¹ 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.
² Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
³ Department of Physiology, Hunan University of Medicine, Huaihua, China.
⁴ 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. Electronic address: zhouyong421@csu.edu.cn.

PMID: 39270890
DOI: 10.1016/j.ijbiomac.2024.135351

Abstract

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.

Keywords: Alveolar epithelial cell; Endoplasmic reticulum stress; Krüppel-like factor 14; Pulmonary fibrosis; Senescence.