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, playing crucial roles in multiple biological processes. FOXO3 is involved in pathways such as autophagy, apoptosis, oxidative stress response, and cell cycle regulation. Its biological effects are often determined by phosphorylation, which can affect its subcellular localization and transcriptional activity. Understanding FOXO3 is important as it is associated with numerous physiological and pathological conditions, and genetic models can help unveil its functions [3].

In hepatocellular carcinoma, inhibition of CDK9 promotes dephosphorylation of SIRT1, leading to FOXO3 protein degradation via acetylation. This inactivates the SIRT1-FOXO3-BNIP3 axis, blocking PINK1-PRKN-mediated mitophagy initiation and enhancing therapeutic effects related to mitochondrial dysfunction [1]. In osteosarcoma, COPS3 upregulates FOXO3 nuclear abundance, promoting autophagosome formation in response to cisplatin, thus contributing to cisplatin resistance. FOXO3, in turn, regulates COPS3 levels, forming a positive feedback loop [2]. In intervertebral disc degeneration, p300 upregulates FOXO3, which inactivates the Wnt/β-catenin pathway, suppressing the progression of the disease [4].

In summary, FOXO3 is a key regulator in multiple biological processes. Model-based research, especially in the context of diseases like hepatocellular carcinoma, osteosarcoma, and intervertebral disc degeneration, has revealed its role in autophagy, mitophagy, and signaling pathway regulation. Understanding FOXO3 through these models provides insights into disease mechanisms and potential therapeutic targets.

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. 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/

3. 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/

4. 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/