Klf15, also known as Krüppel-like factor 15, is a transcription factor that plays crucial roles in multiple biological processes. It is involved in regulating metabolism, including endobiotic and xenobiotic metabolism [7]. It also participates in pathways related to oxidative stress response, cardiac function regulation, and cell phenotype maintenance. Genetic models, such as KO and CKO mouse models, are valuable for studying Klf15's functions.

In skeletal muscle, Klf15 deficiency protects mice from immobility-induced muscle atrophy, indicating its role in this process through the Piezo1/Klf15/IL-6 axis [1]. In the heart, cardiomyocyte-specific WWP1 overexpression, which triggers KLF15 degradation, exacerbates cardiac ischemic injury, while WWP1 inhibition mitigates it, showing Klf15's protective role in cardiac ischemic injury [2]. In pancreatic cancer, Klf15 suppresses cancer stem cell stemness by promoting Nanog degradation [3]. In hypertensive mice, SIRT7 alleviates renal ferroptosis, fibrosis, and injury by facilitating the Klf15/Nrf2 signaling pathway, highlighting Klf15's role in renal protection under hypertensive conditions [4]. In the liver, knockout of hepatocyte Klf15 attenuates rifampicin-induced hepatotoxicity by upregulating Cyp3a11 [5]. In vascular smooth muscle cells, Klf15 deficiency makes mice more susceptible to thoracic aortic dissection, as Klf15 maintains the contractile phenotype of these cells by interacting with MRTFB [6].

In conclusion, Klf15 is essential for maintaining normal physiological functions in multiple tissues. Model-based research, especially using Klf15 KO/CKO mouse models, has revealed its significance in various disease areas such as muscle atrophy, cardiac ischemic injury, pancreatic cancer, hypertensive renal injury, liver injury, and thoracic aortic dissection. These findings suggest that Klf15 could be a potential therapeutic target for these diseases.

References:

1. Hirata, Yu, Nomura, Kazuhiro, Kato, Daisuke, Wake, Hiroaki, Ogawa, Wataru. 2022. A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy. In The Journal of clinical investigation, 132, 1-13. doi:10.1172/JCI154611. https://pubmed.ncbi.nlm.nih.gov/35290243/

2. Lu, Xia, Yang, Boshen, Qi, Ruiqiang, Wang, Yan, Song, Juan. 2023. Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation. In Theranostics, 13, 417-437. doi:10.7150/thno.77694. https://pubmed.ncbi.nlm.nih.gov/36593958/

3. Jiang, Wenna, Liu, Lin, Wang, Meng, Liu, Jing, Ren, Li. 2024. KLF15 suppresses stemness of pancreatic cancer by decreasing USP21-mediated Nanog stability. In Cellular and molecular life sciences : CMLS, 81, 417. doi:10.1007/s00018-024-05442-6. https://pubmed.ncbi.nlm.nih.gov/39367978/

4. Li, Xue-Ting, Song, Jia-Wei, Zhang, Zhen-Zhou, Liu, Xiao-Yan, Zhong, Jiu-Chang. 2022. Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling. In Free radical biology & medicine, 193, 459-473. doi:10.1016/j.freeradbiomed.2022.10.320. https://pubmed.ncbi.nlm.nih.gov/36334846/

5. Hou, Wanqing, Huo, Ku-Geng, Guo, Xiaohua, Ma, Zhenghai, Han, Shuxin. 2024. KLF15-Cyp3a11 Axis Regulates Rifampicin-Induced Liver Injury. In Drug metabolism and disposition: the biological fate of chemicals, 52, 606-613. doi:10.1124/dmd.123.001617. https://pubmed.ncbi.nlm.nih.gov/38670799/

6. Fang, Guangming, Tian, Yexuan, Huang, Shan, Du, Jie, Gao, Shijuan. 2024. KLF15 maintains contractile phenotype of vascular smooth muscle cells and prevents thoracic aortic dissection by interacting with MRTFB. In The Journal of biological chemistry, 300, 107260. doi:10.1016/j.jbc.2024.107260. https://pubmed.ncbi.nlm.nih.gov/38582447/

7. Han, Shuxin, Ray, Jonathan W, Pathak, Preeti, Simon, Daniel I, Jain, Mukesh K. 2019. KLF15 regulates endobiotic and xenobiotic metabolism. In Nature metabolism, 1, 422-430. doi:10.1038/s42255-019-0054-7. https://pubmed.ncbi.nlm.nih.gov/32694878/