FOXO4–p53 protein–protein interaction (null (no widely accepted standard abbreviation for the interaction itself; FOXO4 and p53 are the standard abbreviations for the proteins involved))

The FOXO4–p53 interaction is a direct physical association between the Forkhead DNA-binding domain of FOXO4 and the transactivation domain (TAD) of p53. This complex forms preferentially in senescent cells and stabilizes p53 in the nucleus, upregulating target genes such as p21 and thereby enforcing cell cycle arrest and the senescence phenotype. Disruption of this interaction—either genetically or with tailored synthetic peptides (e.g., FOXO4-DRI)—can cause removal of senescent cells by reactivating p53-dependent apoptosis, representing a promising strategy for treating aging-related disorders and cancers characterized by excessive or abnormal senescence. The interface is structurally dynamic, involving flexible and multiple contact points, making it both a challenging and attractive target for drug design. This target remains an active area of therapeutic research for senolytic interventions, with both opportunities in age-related disease and challenges regarding specificity and safety.

Other names

FOXO4–p53 interfaceFOXO4–p53 complexFOXO4–p53 binding

Inhibitors of the FOXO4–p53 interaction block the capability of FOXO4 to sequester p53 in the nucleus of senescent cells. Disruption leads to the exclusion of p53 from the nucleus, resulting in activation of apoptosis in these cells (senolysis).