Forkhead box protein O1 and Forkhead box protein O3 (FoxO1/3a)

Forkhead box protein O1 (FoxO1) and Forkhead box protein O3 (FoxO3a) are key members of the O-class of forkhead transcription factors that play a central role in regulating the interface between metabolism, cell proliferation, and survival. They are primarily regulated by the PI3K/AKT signaling pathway; phosphorylation by AKT leads to their sequestration in the cytoplasm and subsequent inactivation, while dephosphorylation allows them to translocate to the nucleus to initiate gene transcription. These factors act as critical tumor suppressors by inducing cell cycle arrest and apoptosis in response to cellular stress, but they also regulate metabolic processes such as hepatic gluconeogenesis and lipid metabolism. In oncology, therapeutic strategies often aim to reactivate FoxO1/3a to inhibit tumor growth, whereas in metabolic disorders like type 2 diabetes, FoxO1 inhibition is explored to reduce excessive glucose production. Their involvement in longevity and oxidative stress resistance makes them significant targets for age-related and degenerative diseases.

Other names

FOXO1FOXO3FOXO3aFKHRFKHRL1Forkhead in rhabdomyosarcomaForkhead in rhabdomyosarcoma-like 1

Drugs targeting FoxO1 and FoxO3a typically act by modulating their nuclear-cytoplasmic shuttling, inhibiting their DNA-binding activity, or altering their post-translational modifications such as phosphorylation and acetylation. For instance, AS1842856 is a cell-permeable selective inhibitor that binds to the FoxO1 protein and inhibits its transcriptional activity. Other agents like XPO1 inhibitors (e.g., Selinexor) prevent the nuclear export of FoxO proteins, thereby enhancing their tumor-suppressive transcriptional programs.