Klf4, also known as Krüppel-like factor 4, is a key transcription factor with a zinc-finger-containing structure. It is predominantly expressed in terminally differentiated epithelial tissues and plays crucial roles in numerous physiological and pathological processes. Klf4 is involved in pathways related to cell proliferation, migration, invasion, differentiation, and also has a significant impact on inflammatory responses, metabolic homeostasis, and tumorigenesis [2,3,5,7]. Genetic models, such as KO/CKO mouse models, are valuable tools for studying Klf4's functions.

In lung cancer research, loss of the deubiquitinase USP10 in mice downregulates Klf4 expression and accelerates KrasG12D-driven lung adenocarcinoma initiation and progression, indicating that the USP10-Klf4-TIMP3 axis could be a potential therapeutic target [1]. In endothelial cells, knockdown of Klf4 in an in-vitro model of endothelial senescence (ox-LDL-treated ECs) augmented the senescence-associated secretory phenotype (SASP), while knock-in restored it, revealing Klf4's role in inhibiting SASP through the PDGFRA/NAMPT/mitochondrial ROS pathway [4]. In vascular smooth muscle cells (VSMCs), KLF4 upregulation in atherosclerotic lesions is associated with VSMCs phenotypic switching, and it mediates this through enhancing the metabolic switch to glycolysis by increasing PFKFB3 expression [6].

In conclusion, Klf4 is a multifunctional transcription factor with diverse roles in various biological processes and disease conditions. Studies using mouse models, especially KO/CKO models, have provided insights into its role in cancer (such as lung cancer), endothelial cell senescence, and VSMCs phenotypic switching, highlighting its potential as a therapeutic target in related diseases.

References:

1. Wang, Xingyun, Xia, Shilin, Li, Hongchang, Zhang, Lingqiang, Han, Chuanchun. 2019. The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis. In Cell death and differentiation, 27, 1747-1764. doi:10.1038/s41418-019-0458-7. https://pubmed.ncbi.nlm.nih.gov/31748695/

2. Luo, Xiaoya, Zhang, Yue, Meng, Ying, Ji, Ming, Wang, Yongjun. 2022. Prognostic significance of KLF4 in solid tumours: an updated meta-analysis. In BMC cancer, 22, 181. doi:10.1186/s12885-022-09198-9. https://pubmed.ncbi.nlm.nih.gov/35177016/

3. Liang, Yidan, Zhao, Jiamin, Dai, Tengkun, Zhao, Juanjuan, Xu, Lin. 2024. A review of KLF4 and inflammatory disease: Current status and future perspective. In Pharmacological research, 207, 107345. doi:10.1016/j.phrs.2024.107345. https://pubmed.ncbi.nlm.nih.gov/39134187/

4. Ding, Haoran, Tong, Jing, Lin, Hao, Liu, Xuebo, Chen, Fei. 2024. KLF4 inhibited the senescence-associated secretory phenotype in ox-LDL-treated endothelial cells via PDGFRA/NAMPT/mitochondrial ROS. In Aging, 16, 8070-8085. doi:10.18632/aging.205805. https://pubmed.ncbi.nlm.nih.gov/38728249/

5. Ju, Yunjie, Xiao, Wen, Mathis, Bryan James, Shi, Ying. 2025. KLF4: a multifunctional nexus connecting tumor progression and immune regulation. In Frontiers in immunology, 16, 1514780. doi:10.3389/fimmu.2025.1514780. https://pubmed.ncbi.nlm.nih.gov/39995670/

6. Zhang, Xinhua, Zheng, Bin, Zhao, Lingdan, Liu, Huirong, Wen, Jinkun. 2022. KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells. In Communications biology, 5, 1332. doi:10.1038/s42003-022-04302-y. https://pubmed.ncbi.nlm.nih.gov/36470917/

7. Blum, Andrew, Mostow, Kate, Jackett, Kailey, Ryan, Carly, Hagos, Engda. 2021. KLF4 Regulates Metabolic Homeostasis in Response to Stress. In Cells, 10, . doi:10.3390/cells10040830. https://pubmed.ncbi.nlm.nih.gov/33917010/