Deciphering FOXO3: Functions, Regulation, and Implications in Disease and Therapy

Authors

  • Yue Zhang
  • Rui Zhang

DOI:

https://doi.org/10.54097/89hzqk17

Keywords:

FOXO3, PI3K/Akt Pathway, AMPK Pathway, Longevity, Cancer Therapy

Abstract

Forkhead box O3 (FOXO3) is a critical transcription factor within the FOXO family that regulates various physiological and pathological processes, including metabolism, stress response, apoptosis, and cell cycle control. FOXO3 activity is primarily regulated by post-translational modifications, including phosphorylation, acetylation, and ubiquitination, while interacting with key pathways such as PI3K/Akt and AMPK. These pathways regulate FOXO3's localization and activity within cells, influencing processes like autophagy, oxidative stress resistance, and longevity. FOXO3 also plays a pivotal role in aging, cancer, metabolic regulation, and neurodegenerative diseases. Research highlights FOXO3’s dual role as a tumor suppressor and a contributor to cellular survival under stress, making it an essential target for therapeutic strategies. This review discusses the regulation, biological functions, and therapeutic potential of FOXO3 in various disease contexts.

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References

[1] Orea-Soufi, A., et al., FOXO transcription factors as therapeutic targets in human diseases. Trends Pharmacol Sci, 2022. 43(12): p. 1070-1084.

[2] Link, W., Introduction to FOXO Biology. Methods Mol Biol, 2019. 1890: p. 1-9.

[3] Cao, G., et al., The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sci, 2023. 328: p. 121877.

[4] Renault, V.M., et al., The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene, 2011. 30(29): p. 3207-21.

[5] Bernardo, V.S., F.F. Torres, and D.G.H. da Silva, FoxO3 and oxidative stress: a multifaceted role in cellular adaptation. J Mol Med (Berl), 2023. 101(1-2): p. 83-99.

[6] Sun, X., et al., Peroxiredoxin 1 silencing inhibited the growth and promoted apoptosis of pancreatic cancer cells via targeting FOXO3 gene. Cancer Manag Res, 2018. 10: p. 5019-5026.

[7] Gao, X.W., et al., 17β-Estradiol Prevents Extracellular Matrix Degradation by Downregulating MMP3 Expression via PI3K/Akt/FOXO3 Pathway. Spine (Phila Pa 1976), 2020. 45(5): p. 292-299.

[8] Xie, T., et al., microRNA-582 Potentiates Liver and Lung Metastasis of Gastric Carcinoma Cells Through the FOXO3-Mediated PI3K/Akt/Snail Pathway. Cancer Manag Res, 2020. 12: p. 5201-5212.

[9] Tao, T., et al., Polygonum cuspidatum Extract Exerts Antihyperlipidemic Effects by Regulation of PI3K/ AKT/ FOXO3 Signaling Pathway. Oxid Med Cell Longev, 2021. 2021: p. 3830671.

[10] Qi, S., et al., miR-29a-3p mitigates the development of osteosarcoma through modulating IGF1 mediated PI3k/Akt/FOXO3 pathway by activating autophagy. Cell Cycle, 2022. 21(18): p. 1980-1995.

[11] Peng, Z.Q., et al., Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway. Exp Eye Res, 2024. 244: p. 109919.

[12] Greer, E.L., et al., The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem, 2007. 282(41): p. 30107-19.

[13] Chi, Y., et al., Forkhead box O (FOXO) 3 modulates hypoxia-induced autophagy through AMPK signalling pathway in cardiomyocytes. Biosci Rep, 2016. 36(3).

[14] An, Y., et al., SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop. Cell Death Dis, 2020. 11(2): p. 115.

[15] Xie, Q., et al., Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep, 2012. 13(4): p. 371-7.

[16] Brunet, A., et al., Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 2004. 303(5666): p. 2011-5.

[17] Tao, G.Z., et al., Wnt/β-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3. J Biol Chem, 2013. 288(24): p. 17214-24.

[18] Kahn, A.J., FOXO3 and related transcription factors in development, aging, and exceptional longevity. J Gerontol A Biol Sci Med Sci, 2015. 70(4): p. 421-5.

[19] Sanese, P., et al., FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs. Comput Struct Biotechnol J, 2019. 17: p. 737-745.

[20] Tang, Y.L., et al., Ginsenoside Rg1 protects against Sca-1(+) HSC/HPC cell aging by regulating the SIRT1-FOXO3 and SIRT3-SOD2 signaling pathways in a γ-ray irradiation-induced aging mice model. Exp Ther Med, 2020. 20(2): p. 1245-1252.

[21] Ebrahimnezhad, M., et al., Unveiling the potential of FOXO3 in lung cancer: From molecular insights to therapeutic prospects. Biomed Pharmacother, 2024. 176: p. 116833.

[22] Jeung, Y.J., et al., Shikonin induces apoptosis of lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling antagonized by p300. Biochim Biophys Acta, 2016. 1863(11): p. 2584-2593.

[23] Cao, Y., et al., SIRT3 promotion reduces resistance to cisplatin in lung cancer by modulating the FOXO3/CDT1 axis. Cancer Med, 2021. 10(4): p. 1394-1404.

[24] Wang, X., et al., Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the sirtuin 3-Forkhead box O3a axis in human small-cell lung cancer. Thorac Cancer, 2019. 10(4): p. 642-658.

[25] Guo, Q., et al., microRNA-130b-3p Contained in MSC-Derived EVs Promotes Lung Cancer Progression by Regulating the FOXO3/NFE2L2/TXNRD1 Axis. Mol Ther Oncolytics, 2021. 20: p. 132-146.

[26] Gong, Q., et al., Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling. Oncol Rep, 2018. 40(3): p. 1401-1410.

[27] Chaves, I., et al., Insulin-FOXO3 signaling modulates circadian rhythms via regulation of clock transcription. Curr Biol, 2014. 24(11): p. 1248-55.

[28] Zhang, X., et al., FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis. Am J Hematol, 2014. 89(10): p. 954-63.

[29] Hicks, J.A., et al., Delayed Feeding Alters Transcriptional and Post-Transcriptional Regulation of Hepatic Metabolic Pathways in Peri-Hatch Broiler Chicks. Genes (Basel), 2019. 10(4).

[30] Gilley, J., P.J. Coffer, and J. Ham, FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol, 2003. 162(4): p. 613-22.

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Published

28-04-2025

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