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FOXO4-DRI (Retro-Inverso) is a synthetic, slightly modified version of the standard FOXO4 protein. The modification prolongs half-life of the protein and allows it to interfere with normal FOXO4 function. FOXO4-DRI has been shown in research to prevent normal FOXO4 binding to p53, thereby allowing for elimination of senescent cells, improved organ function, and younger tissue “biological age.” FOXO4-DRI impacts insulin signaling, cell cycle regulation, and oxidative stress signaling pathways. FOXO4-DRI is a cell penetrating peptide shown to selectively induce apoptosis of senescent cells thereby reversing effects of aging in animal studies.

FOXO4-DRI is a cell-permeable peptide comprising part of the p53-interaction domain of FOXO4.  It can compete with endogenous FOXO4 for p53, thereby disrupting the FOXO4-p53 interaction. Disrupting the p53-FOXO4 interaction causes p53 to be excluded from the nucleus and directed to mitochondria for induction of apoptosis in senescent cells, ultimately eliminating senescent fibroblasts through triggering apoptosis[1-2]. FOXO4-DRI to be selective for ionizing radiation-induced senescent IMR90 cells and safe to normal cells. 

[1] Yuzhao Huang. “Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.” Frontiers in Bioengineering and Biotechnology (2021): 677576.
[2] Guihua Liu,  Tingting Li,  Xing Yang. “FOXO4-DRI ALLEVIATES AGE-RELATED TESTOSTERONE SECRETION INSUFFICIENCY VIA TARGETING SENESCENT LEYDIG CELLS IN AGED MICE.” Fertility and sterility (2020).