FOXO4

FOXO4 is a transcription factor belonging to the forkhead box O (FOXO) family and is encoded by the FOXO4 gene in humans. It acts as a central effector of signaling pathways that regulate metabolism, stress resistance, cell cycle progression, and apoptosis.

Regulation and localization: FOXO4 activity is controlled by post-translational modifications, notably phosphorylation by the PI3K/Akt pathway, which promotes 14-3-3 binding and cytoplasmic retention. In response to cellular stress or energy stress, dephosphorylation and/or modification by kinases such as AMPK or JNK promotes nuclear localization and transcriptional activation. Acetylation and deacetylation by p300/CBP and SIRT1, respectively, further modulate its transcriptional program. Subcellular localization thus acts as a switch between growth and stress responses.

Function and targets: In the nucleus, FOXO4 stimulates transcription of genes involved in cell cycle arrest (such as p21 and p27), DNA repair (GADD45), apoptosis (Bim, Fas ligand), and oxidative stress defense (MnSOD, catalase). Through these targets, FOXO4 contributes to senescence, autophagy, and metabolic regulation.

Clinical and research context: FOXO4 is implicated in aging biology and age-related diseases. It can function as a tumor suppressor by limiting proliferation and promoting apoptosis, though context-dependent effects exist. In research aimed at senescence clearance, a peptide inhibitor (FOXO4-DRI) disrupts the FOXO4–p53 interaction to selectively eliminate senescent cells in experimental models.

See also: FOXO family.