FoxO4, a member of the Forkhead box O (FOXO) family of transcription factors [3], plays a crucial role in various cellular processes. It controls genes involved in metabolism, cell cycle, apoptosis, and cellular homeostasis through its transcriptional activity [6]. FoxO4 also mediates cell responses to oxidative stress and antitumor agents [6]. It is regulated by post-translational modifications, interaction with other proteins, and microRNAs [6]. Genetic models, such as gene knockout, are valuable for studying its functions.

In renal ischemia/reperfusion injury, inhibition of Brd4 blocks FoxO4-mediated oxidative stress, reducing endoplasmic reticulum stress-associated and pro-apoptotic protein expression [1]. In vascular smooth muscle cells, the interaction between unspliced XBP1 and FoxO4 maintains the contractile phenotype and prevents aortic aneurysm formation [2]. In zebrafish, deletion of the foxO4 gene increases hypoxia tolerance, as foxO4 -/- zebrafish have lower oxygen consumption and mitochondrial-related activities [5]. In placental development, disruption of Foxo4 in rats leads to placentomegaly, suggesting it is part of a regulatory network controlling hemochorial placenta development [4].

In conclusion, FoxO4 is essential in multiple biological processes. Findings from gene knockout models in different species have revealed its roles in renal injury, aortic aneurysm prevention, hypoxia response, and placental development. These studies contribute to understanding the mechanisms of related diseases and may provide potential therapeutic targets.

References:

1. Liu, Hao, Wang, Lei, Weng, Xiaodong, Chen, Zhiyuan, Liu, Xiuheng. 2019. Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. In Redox biology, 24, 101195. doi:10.1016/j.redox.2019.101195. https://pubmed.ncbi.nlm.nih.gov/31004990/

2. Zhao, Guizhen, Fu, Yi, Cai, Zeyu, Xu, Qingbo, Kong, Wei. 2017. Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction. In Circulation research, 121, 1331-1345. doi:10.1161/CIRCRESAHA.117.311450. https://pubmed.ncbi.nlm.nih.gov/29089350/

3. Link, Wolfgang. . Introduction to FOXO Biology. In Methods in molecular biology (Clifton, N.J.), 1890, 1-9. doi:10.1007/978-1-4939-8900-3_1. https://pubmed.ncbi.nlm.nih.gov/30414140/

4. Kozai, Keisuke, Moreno-Irusta, Ayelen, Iqbal, Khursheed, Parrish, Marc R, Soares, Michael J. 2023. The AKT1-FOXO4 axis reciprocally regulates hemochorial placentation. In Development (Cambridge, England), 150, . doi:10.1242/dev.201095. https://pubmed.ncbi.nlm.nih.gov/36607602/

5. Shi, Linlin, Zhang, Axin, Liu, Hong, Wang, Huanling. 2023. Deletion of the foxO4 Gene Increases Hypoxia Tolerance in Zebrafish. In International journal of molecular sciences, 24, . doi:10.3390/ijms24108942. https://pubmed.ncbi.nlm.nih.gov/37240290/

6. Liu, Wen, Li, Yong, Luo, Bing. 2019. Current perspective on the regulation of FOXO4 and its role in disease progression. In Cellular and molecular life sciences : CMLS, 77, 651-663. doi:10.1007/s00018-019-03297-w. https://pubmed.ncbi.nlm.nih.gov/31529218/