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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.

A cell-penetrating peptide (FOXO4-DRI), which perturbs the FOXO4 interaction with p53, can selectively cause p53 nuclear exclusion and cell-intrinsic apoptosis in senescent cells. Several studies have demonstrated the therapeutic effect of FOXO4-DRI in eliminating senescent cells. FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. FOXO4-DRI improved the testicular microenvironment in naturally aged mice and alleviated age-related testosterone secretion insufficiency. FOXO4 was specifically expressed in human Leydig cells and nuclear translocation in aged human testes. According to the Human Protein Atlas Database, in humans, FOXO4 protein is expressed only in the testis, placenta and muscle. Therefore, special attention must be paid to muscle damage, especially cardiotoxicity during treatment.

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).