Research Peptide · For laboratory research use only
Also known as Proxofim, FOXO4 D-Retro-Inverso peptide
FOXO4-DRI (FOXO4 D-retro-inverso peptide, also listed as Proxofim) is a cell-permeable peptide designed in 2017 to perturb the interaction between the transcription factor FOXO4 and p531. It is built from D-amino acids in retro-inverso order and combines a FOXO4-derived region with a cationic cell-penetrating sequence2.
It is studied as a senolytic research tool, meaning a compound that selectively removes senescent cells. Published work covers mouse models of chemotoxicity and ageing, senescent cell cultures, structural biology, and mouse models of pulmonary fibrosis and pulmonary hypertension1,2,3,4,5,6,7.
As described in the research literature
As described in the research literature, the 2017 study identified FOXO4 as a pivot in senescent cell viability. In senescent cells, the FOXO4 peptide was reported to cause p53 nuclear exclusion and cell-intrinsic apoptosis1. Similar p53 nuclear exclusion was reported in hydrogen peroxide-induced senescent TM3 Leydig cells3 and, for p53 phosphorylated at serine 15, in keloid fibroblasts6.
A 2025 solution NMR study characterised the interaction directly: the disordered FOXO4-DRI binds the disordered p53 transactivation domain 2 and forms a transiently folded complex to which both the FOXO4-derived region and the cell-penetrating sequence contribute, and p53 phosphorylation increased its affinity2.
What published studies have examined
The originating study examined doxorubicin-induced chemotoxicity and both fast-ageing XpdTTD/TTD and naturally aged mice, measuring fitness, fur density and renal function1. Naturally aged mice were later used to examine the testicular microenvironment and testosterone secretion3.
Human chondrocytes expanded in vitro were used to test removal of senescent cells and subsequent cartilage formation in pellet culture4. Keloid organ cultures and fibroblasts were used to examine apoptosis, cell cycle distribution and p53-pS15 localisation6.
A bleomycin-induced pulmonary fibrosis model in mice and activated fibroblasts were used to examine collagen deposition, p53 distribution and extracellular matrix protein content5. In mouse models of pulmonary hypertension, a 2023 study reported that eliminating senescent cells with senolytic interventions, including FOXO4-DRI, was associated with worsened pulmonary haemodynamics and loss of pulmonary endothelial cells7.
Solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and with FOXO4-DRI were reported, including the effect of p53 phosphorylation on binding2.
Sources [2]
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.
Baar MP, Brandt RMC, Putavet DA, et al. Cell, 2017.
The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.
Bourgeois B, Spreitzer E, Platero-Rochart D, et al. Nature Communications, 2025.
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.
Zhang C, Xie Y, Chen H, et al. Aging, 2020.
Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.
Huang Y, He Y, Makarcyzk MJ, et al. Frontiers in Bioengineering and Biotechnology, 2021.
FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice.
Liu Y, Hou Q, Wang R, et al. Naunyn-Schmiedeberg's Archives of Pharmacology, 2023.
FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation.
Kong YX, Li ZS, Liu YB, et al. Communications Biology, 2025.
Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.
Born E, Lipskaia L, Breau M, et al. Circulation, 2023.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.