FOXO4-DRI

Also: FOXO4 D-retro-inverso peptide, Proxofim

Summary

FOXO4-DRI is a synthetic peptide designed in 2017 by a group at Erasmus MC in the Netherlands to kill senescent cells, the damaged cells that stop dividing but accumulate with age. It copies a stretch of the FOXO4 protein but is built from D-amino acids in reverse order, which makes it resistant to breakdown, and carries a cell-penetrating tag. It is a research compound; no human trials have been published.

What it targets

The peptide blocks the interaction between FOXO4 and p53 inside senescent cells, which in the original study caused those cells, and not healthy ones, to undergo programmed cell death. In mice it reduced the toxicity of the chemotherapy drug doxorubicin and was associated with improved fitness, fur density and kidney function in fast-ageing and naturally aged animals. Later studies reported clearance of senescent Leydig cells and higher testosterone in aged mice, reduced markers of blood-vessel ageing in aged mice, and removal of senescent cells from cultured human cartilage cells without improving their ability to form cartilage. All published evidence is in animals or cell culture.

clearing senescent cells (mice, cell culture)chemotherapy toxicity and ageing markers (mice)age-related testosterone decline (mice)vascular ageing (mice)cartilage cell expansion (human cells in culture)

Clinical Research

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging
Baar MP, Brandt RMC, Putavet DA, et al. (2017). Cell. animal cultured senescent cells; fast-ageing (XpdTTD/TTD) and naturally aged mice
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice
Zhang C, Xie Y, Chen H, et al. (2020). Aging. animal senescent TM3 Leydig cells in culture; naturally aged mice
FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway
Hu Z, Li F, Hu C, et al. (2026). Frontiers in Bioengineering and Biotechnology. animal naturally aged and progeroid mice; cultured endothelial cells under oxygen-glucose deprivation
Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes
Huang Y, He Y, Makarcyzk MJ, Lin H (2021). Frontiers in Bioengineering and Biotechnology. in-vitro human cartilage cells from healthy donors, expanded in culture

All research on FOXO4-DRI →