Forkhead box protein O4–Cellular tumor antigen p53 protein–protein interaction interface (FOXO4–p53 PPI)

The FOXO4–p53 protein–protein interaction interface is a therapeutic target focused on the selective elimination of senescent cells, a process known as senolysis (Baar et al., 2017, Cell). In senescent cells, the transcription factor FOXO4 (Forkhead box protein O4) directly interacts with p53, sequestering it within the nucleus and preventing it from initiating apoptosis (UniProt P98177; UniProt P04637). This interaction allows senescent cells to survive and accumulate, contributing to chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). By using competitive inhibitors like the D-retro-inverso peptide FOXO4-DRI (also known as Proxofim), the interaction is disrupted, allowing p53 to translocate to the mitochondria and trigger programmed cell death (Baar et al., 2017). This target is of significant interest in anti-aging medicine and oncology, as clearing these cells has been shown to restore tissue homeostasis and improve healthspan in preclinical models (Guerrero et al., 2019, Aging Cell). Research indicates that targeting this interface can mitigate age-related pathologies such as renal failure and frailty (Zhang et al., 2020, Aging).

Other names

FOXO4-p53 complexFOXO4-p53 interactionFOXO4-p53 interface

The mechanism involves the competitive inhibition of the FOXO4-p53 binding site using a peptide (FOXO4-DRI) that mimics the FOXO4 interaction domain, thereby releasing p53 to translocate from the nucleus to the mitochondria to induce apoptosis (Baar et al., 2017).