FOXO

FOXO refers to a subgroup of the forkhead family of transcription factors, collectively known as the FOXO subfamily. In humans the FOXO genes are FOXO1, FOXO3, FOXO4, and FOXO6. The proteins regulate a range of cellular processes including metabolism, cell cycle arrest, apoptosis, stress resistance, and stem cell maintenance. They share a conserved forkhead DNA-binding domain and act as transcription factors whose activity is controlled by cellular signaling pathways.

Regulation of FOXO activity is governed largely by insulin/IGF-1 signaling through the PI3K-AKT axis. When this pathway is active, AKT phosphorylates FOXO proteins, promoting binding to 14-3-3 proteins and their retention in the cytoplasm, which represses transcriptional activity. Under conditions of reduced growth factor signaling or cellular stress, dephosphorylation allows FOXO to accumulate in the nucleus and activate target genes. FOXO activity is further modulated by post-translational modifications such as acetylation and ubiquitination; acetylation by CBP/p300 can diminish DNA binding, while deacetylation by SIRT1 can enhance stress resistance gene expression. Additional phosphorylation by JNK or MAP kinases can influence localization and activity.

FOXO target genes encompass diverse pathways. They promote gluconeogenic enzymes (for example, PEPCK and G6Pase) in liver, contribute to cell cycle arrest by upregulating p27Kip1 and p21Cip1, and induce apoptosis through proapoptotic genes such as BIM. They also upregulate antioxidant enzymes like MnSOD and catalase, DNA repair factors, and autophagy-related genes such as ULK1, linking metabolic status to cellular survival and maintenance. In many organisms, FOXO factors have been implicated in organismal aging and longevity.

In humans, FOXO1-FOXO4 broadly influence metabolism and cell fate, while FOXO6 shows prominent expression in the brain. DAF-16 and dFOXO are evolutionary homologs in nematodes and flies, illustrating the conserved role of this family in stress responses and longevity.