Klf9, a Krüppel-like factor, is a transcription factor involved in multiple biological processes. It plays key roles in regulating mitochondrial homeostasis, energy metabolism, and cell differentiation. It is associated with pathways such as PPARγ/NRF2, Notch1-mediated signaling, and is crucial for maintaining cellular homeostasis in various cell types [1-10]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying its functions.

Global and cardiac-specific Klf9-deficient mice showed hypertrophic cardiomyopathy, with Klf9 knockout leading to mitochondrial disarray, fragmentation, and impaired respiratory function in cardiomyocytes. It also inhibited mitophagy, accelerating heart failure upon angiotensin II treatment [1]. In diabetic cardiomyopathy, cardiac-specific overexpression of Klf9 deteriorated cardiac function, while silencing Klf9 ameliorated it, and Klf9 regulated PPARγ and NRF2 [2]. In hyperglycemia-aggravated bupivacaine neurotoxicity, Klf9 knockdown improved cell survival and mitochondrial function [3]. KLF9 deficiency protected the heart from inflammatory injury triggered by myocardial infarction by inhibiting NF-κB and MAPK signaling [4]. In dental stem cells, KLF9 promoted osteogenic differentiation by negatively regulating the Notch1-mediated signaling pathway [5]. In cardiomyocytes, Klf9 knockdown inhibited Dex-induced metabolic adaptations [6]. In COPD, inhibition of KLF9 alleviated airway inflammation [7]. In melanoma, Klf9-dependent ROS regulated tumor progression in a stage-specific manner [8]. Depletion of KLF9 compromised the osteogenic differentiation ability of mesenchymal stem cells [9]. KLF9 and KLF13 were important for oligodendrocyte differentiation and myelination [10].

In conclusion, Klf9 is essential for multiple biological functions including mitochondrial homeostasis, cell differentiation, and metabolic adaptations. The study of Klf9 using KO/CKO mouse models has provided insights into its role in diseases such as cardiomyopathy, diabetes-related heart diseases, neurotoxicity, myocardial infarction, and COPD, highlighting its potential as a therapeutic target.

References:

1. Zhang, Lei, Zhang, Menglin, Huang, Jinlong, Zhang, Jun, Chang, Yongsheng. 2024. Klf9 is essential for cardiac mitochondrial homeostasis. In Nature cardiovascular research, 3, 1318-1336. doi:10.1038/s44161-024-00561-6. https://pubmed.ncbi.nlm.nih.gov/39528719/

2. Li, Fangfang, Peng, Jingfeng, Feng, Hui, Qian, Wenhao, Zong, Jing. 2022. KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling. In Cells, 11, . doi:10.3390/cells11213393. https://pubmed.ncbi.nlm.nih.gov/36359788/

3. Li, Hui, Weng, Yaqian, Lai, Luying, Zhang, Yang, Li, Le. 2021. KLF9 regulates PRDX6 expression in hyperglycemia-aggravated bupivacaine neurotoxicity. In Molecular and cellular biochemistry, 476, 2125-2134. doi:10.1007/s11010-021-04059-8. https://pubmed.ncbi.nlm.nih.gov/33547545/

4. Chang, Zhihong, Li, Hongkun. . KLF9 deficiency protects the heart from inflammatory injury triggered by myocardial infarction. In The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27, 177-185. doi:10.4196/kjpp.2023.27.2.177. https://pubmed.ncbi.nlm.nih.gov/36815257/

5. Zhao, Xinyuan, Mai, Zizhao, Lu, Ye, Cui, Li, Yu, Jinhua. . KLF9 Promotes Osteogenic Differentiation of Dental Stem Cells by Negatively Regulating Notch1 Mediated Signaling Pathway. In Frontiers in bioscience (Landmark edition), 28, 85. doi:10.31083/j.fbl2805085. https://pubmed.ncbi.nlm.nih.gov/37258472/

6. Thakkar, Chandni, Alikunju, Saleena, Niranjan, Nandita, Abdellatif, Maha, Sayed, Danish. 2023. Klf9 plays a critical role in GR -dependent metabolic adaptations in cardiomyocytes. In Cellular signalling, 111, 110886. doi:10.1016/j.cellsig.2023.110886. https://pubmed.ncbi.nlm.nih.gov/37690661/

7. Gu, Peijie, Wang, Zhen, Yu, Xin, Li, Yihang, Hu, Xiaodong. . Mechanism of KLF9 in airway inflammation in chronic obstructive pulmonary. In Immunity, inflammation and disease, 11, e1043. doi:10.1002/iid3.1043. https://pubmed.ncbi.nlm.nih.gov/37904708/

8. Bagati, Archis, Moparthy, Sudha, Fink, Emily E, Paragh, Gyorgy, Nikiforov, Mikhail A. 2019. KLF9-dependent ROS regulate melanoma progression in stage-specific manner. In Oncogene, 38, 3585-3597. doi:10.1038/s41388-019-0689-6. https://pubmed.ncbi.nlm.nih.gov/30664687/

9. Xiao, Xiaoxiao, Zhang, Ming, Qian, Yiwei, Wang, Xuepeng, Wu, Qiang. 2024. KLF9 regulates osteogenic differentiation of mesenchymal stem cells. In Journal of molecular histology, 55, 503-512. doi:10.1007/s10735-024-10204-6. https://pubmed.ncbi.nlm.nih.gov/38801643/

10. Bernhardt, Celine, Sock, Elisabeth, Fröb, Franziska, Nemer, Mona, Wegner, Michael. . KLF9 and KLF13 transcription factors boost myelin gene expression in oligodendrocytes as partners of SOX10 and MYRF. In Nucleic acids research, 50, 11509-11528. doi:10.1093/nar/gkac953. https://pubmed.ncbi.nlm.nih.gov/36318265/