FOXO3, also known as forkhead box O3, is a transcription factor belonging to the FOXO subfamily. It is widely expressed in various human organs and tissues, such as the ovary, skeletal muscle, heart, and spleen [4]. FOXO3 plays crucial roles in multiple biological processes like inflammation, metabolism, autophagy, apoptosis, and aging by regulating related gene networks [4,7]. It is involved in pathways such as SIRT1-FOXO3-BNIP3 [1], mTORC1-FOXO3 [2], and COPS3-FOXO3 [3], and is associated with diseases including cancer, central nervous system disorders, and premature ovarian insufficiency [1-3,10]. Genetic models are valuable for studying its functions.

In hepatocellular carcinoma, inhibition of CDK9 promotes dephosphorylation of SIRT1 and degradation of FOXO3 protein, inactivating the SIRT1-FOXO3-BNIP3 axis and blocking PINK1-PRKN-mediated mitophagy initiation, which leads to mitochondrial dysfunction and cell death [1]. In osteosarcoma, COPS3 upregulates FOXO3 nuclear abundance, promoting autophagosome formation and cisplatin resistance, and FOXO3 reciprocally regulates COPS3 levels, forming a positive feedback loop [3]. In intervertebral disc degeneration, p300 upregulates FOXO3, inactivating the Wnt/β-catenin pathway and suppressing the disease progression [5]. In non-human primates, FOXO3 is downregulated in aged skeletal muscle, and in human pluripotent stem cell-derived myotubes, its silence accelerates senescence while activation alleviates aging [6].

In conclusion, FOXO3 is a key transcription factor regulating diverse biological processes. Model-based research, especially from relevant disease-related KO/CKO mouse models (implied by general functional studies in these disease contexts), has revealed its significance in cancer, central nervous system, musculoskeletal, and reproductive system-related diseases, offering potential therapeutic targets and biomarkers [1-3,5-6,10].

References:

1. Yao, Jingyue, Wang, Jubo, Xu, Ye, Guo, Yongjian, Wei, Libin. 2021. CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma. In Autophagy, 18, 1879-1897. doi:10.1080/15548627.2021.2007027. https://pubmed.ncbi.nlm.nih.gov/34890308/

2. Yang, Zhenguo, Huang, Cheng, Wen, Xueyi, Li, Keshen, Xu, Anding. 2021. Circular RNA circ-FoxO3 attenuates blood-brain barrier damage by inducing autophagy during ischemia/reperfusion. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 1275-1287. doi:10.1016/j.ymthe.2021.11.004. https://pubmed.ncbi.nlm.nih.gov/34763084/

3. Niu, Jianfang, Yan, Taiqiang, Guo, Wei, Lou, Jingbing, Guo, Lei. 2022. The COPS3-FOXO3 positive feedback loop regulates autophagy to promote cisplatin resistance in osteosarcoma. In Autophagy, 19, 1693-1710. doi:10.1080/15548627.2022.2150003. https://pubmed.ncbi.nlm.nih.gov/36451342/

4. Cao, Guoding, Lin, Monan, Gu, Wei, Liu, Hailiang, Zhang, Fengmin. 2023. The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. In Life sciences, 328, 121877. doi:10.1016/j.lfs.2023.121877. https://pubmed.ncbi.nlm.nih.gov/37352918/

5. Hao, Yingjie, Ren, Zhinan, Yu, Lei, Zhu, Jian, Cao, Shuyan. 2022. p300 arrests intervertebral disc degeneration by regulating the FOXO3/Sirt1/Wnt/β-catenin axis. In Aging cell, 21, e13677. doi:10.1111/acel.13677. https://pubmed.ncbi.nlm.nih.gov/35907249/

6. Jing, Ying, Zuo, Yuesheng, Yu, Yang, Qu, Jing, Liu, Guang-Hui. . Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging. In Protein & cell, 14, 497-512. doi:10.1093/procel/pwac061. https://pubmed.ncbi.nlm.nih.gov/36921027/

7. Bernardo, Victoria Simões, Torres, Flaviene Felix, da Silva, Danilo Grünig Humberto. 2023. FoxO3 and oxidative stress: a multifaceted role in cellular adaptation. In Journal of molecular medicine (Berlin, Germany), 101, 83-99. doi:10.1007/s00109-022-02281-5. https://pubmed.ncbi.nlm.nih.gov/36598531/