FOXO4-DRI

FOXO4-DRI is a synthetic D-retro-inverso peptide designed to disrupt the interaction between the transcription factor FOXO4 and p53 in senescent cells. It was described in a 2017 Cell paper as a senolytic in mice; human data are absent.

Last reviewed 2026-10-25 by the PeptideWiki editorial team. Editorial policy.

Overview

FOXO4-DRI was described in 2017 by Peter de Keizer and colleagues, then at Erasmus University Medical Center in the Netherlands, in a Cell paper by Baar and co-authors. The researchers reported that the transcription factor FOXO4 helps keep senescent cells alive by binding p53 and holding it in the nucleus, which prevents p53 from triggering apoptosis. A peptide designed to compete with that interaction selectively drove senescent cells into apoptosis in culture and in mice.

Senescent cells accumulate with age and after damage such as chemotherapy, and compounds that eliminate them, called senolytics, are an active research area. In the 2017 study, FOXO4-DRI improved several measures of tissue function in mouse models of chemotherapy toxicity and accelerated or natural aging. The research is preclinical, and no published controlled human trials of FOXO4-DRI exist. It is not approved by the FDA for any use.

Structure

FOXO4-DRI is a D-retro-inverso peptide: it is built from D-amino acids assembled in the reverse order of a segment of the natural FOXO4 protein, a design that approximates the side-chain topology of the parent sequence while resisting protease degradation. In the published design, the FOXO4-derived segment is combined with a cell-penetrating sequence derived from the HIV TAT protein. Exact sequences used in different studies may vary, so the full sequence should always be confirmed from the supplier's documentation or the source publication.

Mechanism

In senescent cells, FOXO4 is reported to bind p53 and retain it in the nucleus, limiting p53-driven apoptosis while the cell remains in growth arrest. FOXO4-DRI is designed to mimic the FOXO4 region involved in this interaction and compete with it. In the 2017 study, disruption of the interaction released active p53, which moved to mitochondria and triggered apoptosis selectively in senescent cells while largely sparing non-senescent cells. Selectivity is thought to reflect the dependence of senescent cells on this survival mechanism. The mechanism has been studied mainly in cultured cells and mice.

Research

Senescent cell clearance in culture

In cultured human fibroblasts made senescent by irradiation or other stressors, FOXO4-DRI reduced viability of senescent cells while having smaller effects on proliferating cells. This selectivity was the basis for describing the peptide as a senolytic. Results depend on cell type and how senescence is induced, and later studies in other cell types have reported varying degrees of selectivity. Selectivity was measured over defined time windows in culture.

Mouse models of chemotoxicity and aging

In the 2017 Cell study, mice treated with FOXO4-DRI after doxorubicin exposure showed reduced markers of senescence and improved liver function measures. In fast-aging and naturally aged mice, treatment was associated with improvements in fur density, physical activity and kidney function markers. These are animal findings from a single foundational study, with additional work by other groups since. Group sizes were modest, and the findings await broader independent replication.

Other senescence models

Subsequent preclinical studies have tested FOXO4-DRI in other contexts, including senescent cells in reproductive tissues and in cartilage or joint models. The findings are preliminary and vary by model. Human evidence is absent, and questions remain about tissue distribution, selectivity and safety in more complex organisms. Delivery, dosing and potential off-target effects of a long cationic D-peptide in tissues have not been well characterized, which limits interpretation of results.

Regulatory status

FOXO4-DRI is not approved by the FDA for any use and was not among the substances reviewed by the FDA's Pharmacy Compounding Advisory Committee in July 2026. No regulatory approvals are known elsewhere; check current status locally. It is handled as a research compound. For sport, check the current WADA Prohibited List.

Status changes often. See the regulatory tracker for dated updates.

Quality and identity testing

A FOXO4-DRI certificate of analysis should confirm identity by mass spectrometry against the expected mass shown on this page and report HPLC purity. Because this is a long peptide made entirely of D-amino acids, standard MS cannot confirm stereochemistry; chiral amino acid analysis is needed to show that the material is the D-form rather than an all-L or mixed product. Long syntheses produce deletion and truncation impurities, which should be addressed. The certificate should state the exact sequence, including any cell-penetrating segment, along with salt form and net peptide content. Arginine-rich sequences carry many counter-ions.

For a walkthrough of each section of a certificate, see how to read a COA.

Storage and stability

Store lyophilized FOXO4-DRI sealed at -20 °C or below, protected from light and moisture. D-amino acid peptides resist proteolysis, but they remain subject to chemical degradation and moisture uptake. Arginine-rich cationic peptides can aggregate or adsorb to surfaces in solution, so use low-binding labware, prepare solutions close to use, aliquot them and avoid repeated freeze-thaw cycles.

Download the FOXO4-DRI data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.

Latest research

Frequently asked questions

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References

1. Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017. Find on PubMed
2. PubMed: all indexed literature on FOXO4-DRI
3. ClinicalTrials.gov: registered studies mentioning FOXO4-DRI