Forkhead box protein O (FOXO) transcription factors (FOXO)

Forkhead box protein O (FOXO) transcription factors are a conserved family of proteins, including FOXO1, FOXO3, FOXO4, and FOXO6, that play a central role in maintaining cellular homeostasis by regulating genes involved in cell cycle arrest, apoptosis, and oxidative stress resistance [1, 5, 15]. They act as critical downstream effectors of the PI3K/Akt/mTOR signaling pathway, where phosphorylation by Akt leads to their nuclear export and inactivation [10, 12]. When active in the nucleus, FOXO factors function as tumor suppressors by inducing programmed cell death and inhibiting proliferation in response to stress [5, 16]. Beyond oncology, FOXO1 is a major regulator of hepatic gluconeogenesis and insulin sensitivity, while FOXO3 is strongly associated with human longevity and stem cell maintenance [8, 10, 13]. Therapeutic strategies currently explore activating FOXO to combat cancer and aging-related diseases, or inhibiting specific isoforms like FOXO1 to treat metabolic disorders such as type 2 diabetes [3, 10].

Other names

Forkhead box Class OForkhead in rhabdomyosarcoma (FKHR)FKHRL1AFXAF6q21DAF-16

Inhibition of nuclear export via PI3K/Akt pathway inhibition to promote transcriptional activity; Direct inhibition of FOXO1 DNA binding; Disruption of protein-protein interactions (e.g., FOXO4-p53) to induce apoptosis in senescent cells.