Forkhead box protein O4–Tumor protein p53 protein–protein interface (FOXO4–p53 PPI) (FOXO4–p53 PPI)

The FOXO4–p53 protein–protein interface is a critical regulatory node in the maintenance of cellular senescence (Baar et al., 2017, Cell). In senescent cells, FOXO4 binds to p53 and sequesters it in the nucleus, preventing it from localizing to the mitochondria where it would otherwise trigger apoptosis (Zhang et al., 2020, Aging). By maintaining this interaction, senescent cells avoid programmed cell death and persist in tissues, contributing to chronic inflammation and age-related decline through the secretion of the senescence-associated secretory phenotype (SASP) (He & Sharpless, 2017, Cell). Therapeutic targeting of this interface aims to disrupt the binding, allowing p53 to induce apoptosis specifically in senescent cells, a strategy known as senolysis (Baar et al., 2017, Cell). The most prominent agent targeting this interface is the FOXO4-DRI peptide (also known as Proxofim), which has shown efficacy in clearing senescent cells and restoring tissue function in preclinical models of aging and chemotherapy-induced damage (Baar et al., 2017, Cell). This target represents a promising avenue for treating age-related diseases and improving healthspan by selectively eliminating deleterious senescent cell populations (Guerrero et al., 2019, Aging Cell).

Other names

FOXO4-p53 interactionFOXO4-p53 complexForkhead box O4-p53 interface

Disruption of the FOXO4–p53 interaction to release p53 from the nucleus to the mitochondria, thereby inducing p53-mediated apoptosis specifically in senescent cells (Baar et al., 2017, Cell).