FOXO4-DRI

FOXO4-DRI is a synthetic D-retro-inverso peptide (C228H388N86O64, approximately 5,358 g/mol) derived from the transcription factor FOXO4. Retro-inverso analogs present the parent sequence in reverse order and are built from D-amino acids in place of L-amino acids, a configuration that common proteases do not readily recognize. The peptide was designed in 2017 to perturb the interaction between FOXO4 and p53, and it combines a FOXO4-derived region with a cationic cell-permeability peptide sequence.

FOXO4-DRI in the research literature

In the 2017 study that introduced it, the peptide selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis in senescent cells in culture, and it was subsequently examined in XpdTTD/TTD progeroid mice and naturally aged mice. A 2025 solution NMR study reported that the intrinsically unstructured FOXO4-DRI binds the similarly unstructured p53 transactivation subdomain TAD2, forming a transiently folded complex to which both the FOXO4-derived region and the cell-permeability peptide contribute; p53 phosphorylation increased affinity for both FOXO4 and FOXO4-DRI.

Other senescent-cell models include expanded chondrocyte cultures, in which the peptide removed more than half of late-passage (PDL9) cells without significantly affecting early-passage (PDL3) cell numbers, and senescent endothelial cells, where co-immunoprecipitation showed that it blocked FOXO4 binding to p53, with subsequent BAX and cleaved caspase-3 induction.