FOXO1FOXO4

FOXO1FOXO4 denotes the family of Forkhead box O (FOXO) transcription factors in humans, including FOXO1, FOXO3, FOXO4, and FOXO6. These proteins function as sequence-specific transcription factors that regulate a broad set of genes involved in metabolism, cell cycle control, apoptosis, DNA repair, and cellular stress resistance. They respond to nutritional and hormonal cues, growth factor signaling, and oxidative stress to coordinate cellular fate and energy homeostasis.

Regulation of FOXO activity is governed primarily by subcellular localization and post-translational modifications. In the presence of insulin or growth factor signaling, PI3K/AKT kinase activity phosphorylates FOXO proteins, promoting binding to 14-3-3 proteins and their retention in the cytoplasm, which suppresses transcriptional activity. Stress signals or energy deprivation activate phosphatases and kinases such as JNK, MST1, and AMPK, leading to dephosphorylation and nuclear translocation where FOXOs activate target genes. Additional modifications, including acetylation by p300/CBP and deacetylation by SIRT1, SUMOylation, and other phosphorylation events, further modulate DNA binding and transcriptional output.

Key target genes include those promoting cell cycle arrest and repair (CDKN1A/p21, CDKN1B/p27), apoptosis (BCL2L11/Bim, FasL), and stress response enzymes (GADD45, MnSOD/SOD2, Catalase). Through these targets, FOXOs influence aging, metabolism, tumor suppression, and responses to oxidative stress. In disease contexts, FOXO signaling can act as a tumor suppressor or, under certain conditions, contribute to cell survival and therapy resistance, highlighting the complexity of FOXO biology. Therapeutic strategies aim to modulate FOXO activity to treat metabolic disorders, cancer, and neurodegenerative diseases. Although related, individual family members exhibit tissue-specific expression and distinct, sometimes overlapping, functional roles.