Klf14, a member of the Krüppel-like factor family, is a master trans-regulatory gene with multiple biological functions [5]. It is involved in various pathways such as lipid and glucose metabolism, cell apoptosis, proliferation, and differentiation [5]. Genetic models, like gene knockout (KO) mouse models, have been crucial in studying Klf14's functions.

In sepsis, Klf14 deletion led to increased murine mortality. It regulates macrophage glycolysis and immune function by inhibiting HK2 transcription, decreasing glycolysis and inflammatory cytokine secretion [1]. In renal fibrosis, KLF14 -/- mice showed more severe fibrosis after unilateral ureteral obstruction. KLF14 can target PPARα as a transcriptional activator, enhancing fatty acid oxidation and reducing fibrosis [3]. In hepatocellular carcinoma, downregulation of Klf14 was correlated with poor prognosis. Overexpression of Klf14 suppressed cell growth by modulating iron homeostasis through repression of IRP2 [4]. In cervical cancer, overexpression of Klf14 induced S-phase arrest via activating the JNK-signaling pathway, and also promoted ferroptosis by downregulating GPX4 [2,6]. In breast cancer, Klf14 was downregulated, and its overexpression inhibited cell invasion and M2 macrophage polarization through modulating the SOCS3/RhoA/Rock/STAT3 signaling [7].

In conclusion, Klf14 plays essential roles in multiple biological processes and disease conditions. KO mouse models have significantly contributed to understanding its functions in sepsis, renal fibrosis, hepatocellular carcinoma, cervical cancer, and breast cancer. These findings suggest Klf14 could be a potential therapeutic target for these diseases.

References:

1. Yuan, Yuan, Fan, Guangjian, Liu, Yuqi, Chen, Feng, Li, Jingbao. 2022. The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis. In Cellular & molecular immunology, 19, 504-515. doi:10.1038/s41423-021-00806-5. https://pubmed.ncbi.nlm.nih.gov/34983946/

2. Ye, Hui, Ding, XuChao, Lv, XinRan, Li, RuoNan, Cao, LiLi. 2024. KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer. In Journal of translational medicine, 22, 923. doi:10.1186/s12967-024-05714-6. https://pubmed.ncbi.nlm.nih.gov/39390559/

3. Chen, Lei, Sha, Ming-Lei, Chen, Fei-Teng, Fan, Guang-Jian, Shao, Yi. 2022. Upregulation of KLF14 expression attenuates kidney fibrosis by inducing PPARα-mediated fatty acid oxidation. In Free radical biology & medicine, 195, 132-144. doi:10.1016/j.freeradbiomed.2022.12.096. https://pubmed.ncbi.nlm.nih.gov/36584797/

4. Zhou, Hui, Chen, Junru, Fan, Mingjie, Zheng, Shusen, Yan, Qingfeng. 2023. KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2. In Journal of experimental & clinical cancer research : CR, 42, 5. doi:10.1186/s13046-022-02562-4. https://pubmed.ncbi.nlm.nih.gov/36600258/

5. Akash, Muhammad Sajid Hamid, Rasheed, Sumbal, Rehman, Kanwal, Imran, Muhammad, Assiri, Mohammed A. 2023. Biochemical Activation and Regulatory Functions of Trans-Regulatory KLF14 and Its Association with Genetic Polymorphisms. In Metabolites, 13, . doi:10.3390/metabo13020199. https://pubmed.ncbi.nlm.nih.gov/36837818/

6. Du, Ying, Ye, Hui, Lin, Mei, Cao, Lili. 2023. KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells. In Frontiers in immunology, 14, 1267950. doi:10.3389/fimmu.2023.1267950. https://pubmed.ncbi.nlm.nih.gov/38143751/

7. Chu, Jian, Hu, Xing-Chi, Li, Chang-Chun, Fan, Hui-Wen, Jiang, Guo-Qin. 2022. KLF14 alleviated breast cancer invasion and M2 macrophages polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling. In Cellular signalling, 92, 110242. doi:10.1016/j.cellsig.2022.110242. https://pubmed.ncbi.nlm.nih.gov/34998931/