FOXO4-DRI
Engineered D-retro-inverso peptide that disrupts the interaction between FOXO4 and p53 within senescent cells, triggering p53-mediated apoptosis selectively in the senescent fraction.
FOXO4-DRI is a synthetic peptide composed entirely of D-amino acids in a retro-inverso configuration, derived from the FOXO4 transcription factor (residues 86-101 of the FOXO4 protein). It was introduced by Baar and colleagues at Erasmus MC in 2017 as a candidate senolytic — a class of compounds that selectively eliminate senescent cells while sparing healthy ones.
The mechanism exploits a vulnerability specific to the senescent state. In senescent cells, FOXO4 sequesters activated p53 in the nucleus, preventing p53-mediated apoptosis and allowing the cells to persist in their pro-inflammatory state. FOXO4-DRI competitively disrupts the FOXO4–p53 interaction, releasing p53 to execute apoptosis. Because non-senescent cells do not depend on this FOXO4–p53 sequestration for survival, the peptide is effectively cytotoxic only to the senescent fraction.
In aged and progeroid mice, FOXO4-DRI administration restored fitness markers (fur density, kidney function, exercise capacity) that paralleled reductions in senescent-cell burden. The peptide is investigational and remains a research tool rather than a clinical agent; first-generation clinical trials of FOXO4-targeted senolytics are early-stage.