Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Changsha, Hunan, 410011, China.
Respir Res. 2024 Apr 10;25(1):160. doi: 10.1186/s12931-024-02781-7.
No effective therapies for pulmonary fibrosis (PF) exist because of the unclear molecular pathogenesis and the lack of effective therapeutic targets. Zinc finger protein 451 (ZNF451), a transcriptional regulator, plays crucial roles in the pathogenesis of several diseases. However, its expression pattern and function in PF remain unknown. This study was designed to investigate the role of ZNF451 in the pathogenesis of lung fibrosis.
GEO dataset analysis, RT‒PCR, and immunoblot assays were used to examine the expression of ZNF451 in PF; ZNF451 knockout mice and ZNF451-overexpressing lentivirus were used to determine the importance of ZNF451 in PF progression; and migration assays, immunofluorescence staining, and RNA-seq analysis were used for mechanistic studies.
ZNF451 is downregulated and negatively associated with disease severity in PF. Compared with wild-type (WT) mice, ZNF451 knockout mice exhibited much more serious PF changes. However, ZNF451 overexpression protects mice from BLM-induced pulmonary fibrosis. Mechanistically, ZNF451 downregulation triggers fibroblast activation by increasing the expression of PDGFB and subsequently activating PI3K/Akt signaling.
These findings uncover a critical role of ZNF451 in PF progression and introduce a novel regulatory mechanism of ZNF451 in fibroblast activation. Our study suggests that ZNF451 serves as a potential therapeutic target for PF and that strategies aimed at increasing ZNF451 expression may be promising therapeutic approaches for PF.
由于肺纤维化（PF）的分子发病机制尚不清楚，且缺乏有效的治疗靶点，目前尚无有效的治疗方法。锌指蛋白 451（ZNF451）作为一种转录调节因子，在多种疾病的发病机制中发挥着关键作用。然而，其在 PF 中的表达模式和功能尚不清楚。本研究旨在探讨 ZNF451 在肺纤维化发病机制中的作用。
利用 GEO 数据集分析、RT-PCR 和免疫印迹检测 PF 中 ZNF451 的表达；利用 ZNF451 敲除小鼠和 ZNF451 过表达慢病毒来确定 ZNF451 在 PF 进展中的重要性；利用迁移实验、免疫荧光染色和 RNA-seq 分析进行机制研究。
ZNF451 在 PF 中表达下调，与疾病严重程度呈负相关。与野生型（WT）小鼠相比，ZNF451 敲除小鼠的 PF 变化更为严重。然而，ZNF451 过表达可保护小鼠免受博来霉素诱导的肺纤维化。机制上，ZNF451 的下调通过增加 PDGFB 的表达并随后激活 PI3K/Akt 信号来触发成纤维细胞的激活。
这些发现揭示了 ZNF451 在 PF 进展中的关键作用，并提出了 ZNF451 调节成纤维细胞激活的新机制。我们的研究表明，ZNF451 可作为 PF 的潜在治疗靶点，增加 ZNF451 表达的策略可能是 PF 的一种有前途的治疗方法。
