Klf6, a member of the Krüppel-like factors (KLFs) family of C2/H2 zinc finger DNA-binding proteins, plays crucial roles in multiple biological processes such as proliferation, metabolism, inflammation, and injury responses [1,4]. It is involved in various pathways, for example, regulating autophagy through the mTOR/ULK1 pathway and Beclin1 transcription, and interacting with the STAT3 pathway [1,2].

In a mouse model of hepatic ischemia-reperfusion (I/R) injury, KLF6 deficiency exacerbated liver damage, cell apoptosis, and hepatic inflammatory responses, while overexpression had the opposite effects. Mechanistically, KLF6 inhibited over-activation of autophagy at the initial stage, indicating its protective role in I/R injury [1]. In a myocardial I/R injury model, Klf6 knockdown restrained H/R-triggered cell viability loss, improved I/R-induced myocardial injury, and inhibited ferroptosis, as Klf6 was shown to directly bind to the Acsl4 promoter and positively regulate its expression [3]. In a male murine model of diabetic kidney disease (DKD), podocyte-specific induction of human KLF6 attenuated podocyte loss, PT dysfunction, and interstitial fibrosis, as it triggered the release of secretory ApoJ to activate calcium/calmodulin-dependent protein kinase 1D (CaMK1D) signaling in neighboring PT cells [5]. In thymic epithelial cells (TEC) of mice, Klf6 deficiency led to a hypoplastic thymus, increased apoptotic TEC, and affected T cell development, indicating its prosurvival role and importance in TEC subset development [6].

In conclusion, Klf6 has diverse functions in different tissues and disease conditions. Gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its significance in hepatic I/R injury, myocardial I/R injury, DKD, and thymus development. Understanding Klf6's functions through these model-based studies provides insights into the underlying mechanisms of these diseases and potential therapeutic targets.

References:

1. Li, Jiye, Yu, Dongsheng, He, Chenhui, Zhang, Yi, Zhang, Shuijun. 2023. KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy. In Cell death & disease, 14, 393. doi:10.1038/s41419-023-05872-3. https://pubmed.ncbi.nlm.nih.gov/37391422/

2. Tian, Siyuan, Zhou, Xia, Zhang, Miao, Wang, Jingbo, Han, Ying. 2022. Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages. In Stem cell research & therapy, 13, 330. doi:10.1186/s13287-022-03010-y. https://pubmed.ncbi.nlm.nih.gov/35858897/

3. Qiu, Ma-Li, Yan, Wei, Liu, Mo-Mu. 2023. Klf6 aggravates myocardial ischemia/reperfusion injury by activating Acsl4-mediated ferroptosis. In The Kaohsiung journal of medical sciences, 39, 989-1001. doi:10.1002/kjm2.12733. https://pubmed.ncbi.nlm.nih.gov/37530646/

4. Syafruddin, Saiful E, Mohtar, M Aiman, Wan Mohamad Nazarie, Wan Fahmi, Low, Teck Yew. 2020. Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology. In Biomolecules, 10, . doi:10.3390/biom10101378. https://pubmed.ncbi.nlm.nih.gov/32998281/

5. Gujarati, Nehaben A, Frimpong, Bismark O, Zaidi, Malaika, Guo, Yiqing, Mallipattu, Sandeep K. 2024. Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease. In Nature communications, 15, 8038. doi:10.1038/s41467-024-52306-5. https://pubmed.ncbi.nlm.nih.gov/39271683/

6. Malin, Justin, Martinez-Ruiz, Gustavo Ulises, Zhao, Yongge, Allman, David, Bhandoola, Avinash. 2023. Expression of the transcription factor Klf6 by thymic epithelial cells is required for thymus development. In Science advances, 9, eadg8126. doi:10.1126/sciadv.adg8126. https://pubmed.ncbi.nlm.nih.gov/37967174/