FOXO4-DRI Research, Specifications & Scientific Information

Introduction

FOXO4-DRI is a designed molecule with a single, precisely stated job: to prevent the transcription factor FOXO4 from holding p53 where senescent cells need it. Senescent cells accumulate with age and after cytotoxic stress; they resist apoptosis; and a 2017 paper in Cell identified FOXO4 as the pivot on which that resistance turns, then built a peptide to break it ^[1].

What followed is unusual in this library in two ways. First, the mechanism was not left as a hypothesis — solution nuclear magnetic resonance has since resolved the peptide bound to the disordered transactivation domain of p53, and shown which parts of the molecule contribute ^[2]. Few compounds here have structural evidence of that quality.

Second, the literature contains a substantial result pointing the other way. A 2023 study in Circulation removed senescent pulmonary endothelial cells by several methods including this peptide, and found pulmonary haemodynamics got worse rather than better ^[3]. That finding is reported on this page at the same weight as the favourable ones, because the premise the whole field rests on — that senescent cells are a burden to be cleared — is exactly what it qualifies.

There is no human study of this compound. None is registered.

What Is FOXO4-DRI?

FOXO4-DRI is a synthetic peptide of roughly forty-eight residues, built as a D-retro-inverso construct: D-amino acids assembled in the reverse order of the parent sequence, so that the spatial arrangement of the side chains is approximately preserved while the backbone is not one that ordinary proteases recognise. The molecule has two functional parts — a region derived from FOXO4 and a cationic cell-permeability sequence — and both of them contribute to binding the target ^[2].

PubChem carries it under compound identifier 167312269 with CAS registry number 2460055-10-9, molecular formula C228H388N86O64 and average mass 5358 g/mol. No public register publishes its residue sequence in single-letter code, so the sequence and residue-count fields in the specification table below are left unfilled rather than transcribed from a supplier listing.

Its status is preclinical, unambiguously. It has not been approved by the U.S. Food and Drug Administration for any indication; no marketing application is on record in the United States; no clinical trial of it is registered on ClinicalTrials.gov; and no human study of it appears in the indexed literature.

FOXO4-DRI Specifications

PubChem carries the peptide under compound identifier 167312269 with CAS registry number 2460055-10-9, and a second record, 168431240, gives the same molecular formula C228H388N86O64 and the same average mass of 5358 g/mol; the first is annotated as a trifluoroacetate salt form, which is how synthetic peptides of this length are ordinarily isolated. No public register publishes the residue sequence in single-letter code, so the sequence and residue-count fields are left unfilled rather than transcribed from a supplier listing. What the primary literature does state about the structure is specific: the molecule is a D-retro-inverso peptide — built from D-amino acids in reversed order, so that the side-chain topology of the parent sequence is approximately preserved while the backbone is not a substrate for ordinary proteases — and it comprises a FOXO4-derived region together with a cationic cell-permeability peptide, both of which contribute to binding p53. The formula corresponds to roughly forty-eight residues, and the mass of a trifluoroacetate-salt lot will exceed the free-peptide figure.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does FOXO4-DRI Work?

The reasoning behind the molecule is worth setting out in order, because it is a rare case in this field of a compound designed from a mechanism rather than a mechanism proposed for a compound.

Senescent cells stop dividing but do not die. They persist, and they secrete a characteristic mixture of inflammatory mediators. Genetic clearance of senescent cells had already been shown to delay features of ageing in mice, which raised the question the 2017 work set out to answer: how do these cells avoid the apoptosis that their level of damage should trigger ^[1]?

The answer identified was FOXO4. In senescent cells, FOXO4 binds p53 and keeps it in the nucleus, where it supports the senescent state rather than driving apoptosis. A peptide that occupies p53's binding surface in FOXO4's place therefore releases p53 to leave the nucleus — and in a cell already carrying the damage load of senescence, that is sufficient to trigger cell-intrinsic apoptosis. In a non-senescent cell it is not, which is where the selectivity comes from ^[1].

The structural work that followed confirmed the interaction and complicated the picture in an interesting way. Both binding partners are intrinsically disordered, and the complex they form is described as transiently folded — an association that orders itself only on contact, rather than a lock-and-key fit. Both halves of the peptide participate, the FOXO4-derived region and the cationic permeability sequence alike, so the import tag is not inert cargo. And phosphorylation of p53 increases its affinity for both FOXO4 and the peptide, which links the interaction to the DNA-damage signalling that produces senescence in the first place ^[2].

FOXO4-DRI Mechanism of Action

In vitro research

Selective apoptosis in senescent cells. The peptide perturbs the FOXO4–p53 interaction; in senescent cells this selectively causes nuclear exclusion of p53 and cell-intrinsic apoptosis ^[1].

Structural characterisation of the complex. Solution NMR structural models were solved for the p53 transactivation domain bound to the FOXO4 forkhead domain and, separately, bound to the peptide. The disordered peptide and the disordered p53TAD2 form a transiently folded complex; both the FOXO4-derived region and the cationic cell-permeability peptide contribute to the interaction; and p53 phosphorylation enhances affinity for both FOXO4 and the peptide ^[2]. Several authors of that work disclose shares in a company developing compounds in this area and a published patent covering related methods, which is stated in the paper and is stated here.

Human chondrocytes expanded in culture. The peptide was reported to remove senescent cells selectively from human chondrocytes expanded in vitro — a setting where senescence during expansion is a practical obstacle rather than a disease model ^[5].

Keloid fibroblasts. In senescent keloid fibroblasts, apoptosis was reported to follow nuclear exclusion of p53 with upregulated serine-15 phosphorylation, which is consistent with the mechanism described above and identifies the phosphorylation site involved ^[6].

Findings in this section were obtained in cultured cells and in cell-free structural systems. Nothing in them establishes anything about intact animals or about humans.

What Is FOXO4-DRI Being Researched For?

• Senolysis as a general strategy — the elimination of senescent cells as a route to restoring tissue function after cytotoxic stress or in ageing ^[1].
• Chemotoxicity — neutralisation of doxorubicin-induced toxicity in mice ^[1].
• Age-related testicular endocrine function — senescent Leydig cells and testosterone secretion in aged mice ^[4].
• Fibrosis — bleomycin-induced pulmonary fibrosis in mice, through myofibroblast targeting ^[7].
• Cell-therapy manufacturing — removal of senescent cells from expanded human chondrocyte preparations ^[5].
• Dermal fibroproliferative disease — keloid fibroblasts in culture ^[6].
• The limits of senolysis — pulmonary vascular disease, where clearing senescent cells made the condition worse ^[3].

None of that research is research into, or evidence about, research-grade material supplied for laboratory use.

Preclinical Research on FOXO4-DRI

Animal research

The 2017 mouse work

Design and result as reported. Under conditions described as well tolerated in vivo, the peptide neutralised doxorubicin-induced chemotoxicity in mice. In both fast-ageing XpdTTD/TTD mice and naturally aged mice, it was reported to restore fitness, fur density and renal function ^[1].

Weight. This is the result the compound is known for, and it is a strong one: three separate functional measures, in two different mouse models, from a laboratory that then published the mechanism behind it. It is also mouse data on a molecule with no human exposure of any kind.

Testicular endocrine function in aged mice

Design and result as reported. Senescent Leydig cells were targeted in aged mice, with reported alleviation of age-related insufficiency in testosterone secretion ^[4]. A later study from the same area reported improved spermatogenesis in aged mice attributed to reduced senescence-associated secretory phenotype output from Leydig cells.

Limitations. Single laboratories, aged-mouse models, and endpoints measured in the animal rather than followed to any functional consequence.

Pulmonary fibrosis

Design and result as reported. In bleomycin-induced pulmonary fibrosis in mice, a FOXO4 peptide was reported to target myofibroblasts and ameliorate fibrosis, with the effect attributed to extracellular matrix–receptor interaction pathways ^[7].

The result that points the other way: pulmonary hypertension

Design. Senescent-cell clearance was achieved by four independent methods — a p16 promoter-driven suicide gene in p16-ATTAC mice, the senolytic drug ABT263, this peptide, and p16 inactivation — across mouse models of hypoxia, hypoxia plus Sugen, serotonin-transporter overexpression, and monocrotaline-treated rats ^[3].

Result as reported. Senescent-cell elimination raised right ventricular systolic pressure and the hypertrophy index, increased vessel remodelling, and markedly decreased pulmonary endothelial cells. Haemodynamic deterioration and endothelial cell loss occurred in serotonin-transporter-overexpressing mice given either ABT263 or this peptide. In monocrotaline rats, ABT263 slightly reduced severity at one week and aggravated it at three ^[3].

Why it matters more than its length here suggests. The finding is not a tolerability signal attached to one molecule; it is evidence that in one vascular bed the senescent cells being removed were load-bearing. The authors conclude that senolytic interventions may worsen pulmonary haemodynamics and invite consideration of that risk in any strategy aimed at controlling senescence. A page that reported only the favourable rodent findings would be describing a different literature from the one that exists.

Findings described in this section were observed in mice and rats. Nothing in them establishes anything about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

FOXO4-DRI vs Related Compounds

Against small-molecule senolytics

ABT263 (navitoclax) and the dasatinib–quercetin combination are the compounds most of the senolytic literature uses, and they act on BCL-2 family proteins rather than on FOXO4. The pulmonary hypertension study used ABT263 and this peptide side by side and found the same direction of effect from both ^[3], which supports the reading that the problem lies with clearing the cells rather than with either molecule.

Against the longevity peptides in this library

Epitalon and N-Acetyl Epitalon are associated with ageing research through a telomere hypothesis and a Russian research programme. This peptide comes from a different tradition entirely — a named protein–protein interaction, a structure-based design, and publication in Cell and Nature Communications. The evidentiary standards are not comparable, and neither are the compounds.

Against mitochondrial peptides

SS-31 addresses a different proposed driver of ageing, mitochondrial function, with a different molecular target. Grouping them under longevity describes an intention, not a mechanism.

Its own distinguishing feature

Of the compounds on this site associated with ageing research, this is the one whose target interaction has been resolved structurally ^[2] and the one with no human exposure at all. Those two facts sit together and both belong in any account of it.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

A mirror-image peptide. D-retro-inverso construction means every residue is the D enantiomer and the sequence runs backwards relative to the parent. The geometric consequence is that side chains occupy approximately the positions they would in the natural peptide while the amide bonds are reversed, so proteases that recognise L-peptide backbones do not act on it. The design intent is longevity in a biological medium; no pharmacokinetic measurement confirming it is published for this molecule.

Two functional halves, not one plus a tag. The structural work found that the cationic cell-permeability sequence contributes to p53 binding along with the FOXO4-derived region ^[2]. A truncated construct retaining only the FOXO4-derived part is therefore not a minimal version of this molecule; it is a different one.

No published sequence in a public register. PubChem gives formula and mass but no single-letter sequence, and no UNII resolves for the substance. Sequence and residue-count fields on this page are left unfilled in consequence. For a peptide of this length that is a material gap: sequence is what makes independent identity confirmation possible, and without it a purchaser is relying on the supplier's own description.

Salt form changes the number on the certificate. One of the two PubChem records is annotated as a trifluoroacetate salt form, which is how synthetic peptides of this length are ordinarily isolated. Trifluoroacetate contributes substantially to the mass of a ~5.4 kDa peptide carrying many basic residues, and a purity or mass figure that does not state the counter-ion and water content is incomplete.

Length brings the usual synthesis burden. At roughly forty-eight residues the molecule sits at the upper end of solid-phase synthesis, where deletion sequences differing from the target by one residue are the characteristic impurity. Such species are close enough in mass and in chromatographic behaviour that resolving them requires a method designed for the purpose, and an all-D peptide cannot be checked by the enzymatic digests used to confirm long L-peptides.

Frequently Asked Questions

Scientific 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. PMID 28340339 doi:10.1016/j.cell.2017.02.031
2. Bourgeois B, Spreitzer E, Platero-Rochart D, et al.. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI Nature communications; 2025. PMID 40593617 doi:10.1038/s41467-025-60844-9
3. Born E, Lipskaia L, Breau M, et al.. Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression Circulation; 2023. PMID 36515093 doi:10.1161/CIRCULATIONAHA.122.058794
4. Zhang C, Xie Y, Chen H, et al.. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice Aging; 2020. PMID 31959736 doi:10.18632/aging.102682
5. Huang Y, He Y, Makarcyzk MJ, et al.. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes Frontiers in bioengineering and biotechnology; 2021. PMID 33996787 doi:10.3389/fbioe.2021.677576
6. Kong YX, Li ZS, Liu YB, et al.. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation Communications biology; 2025. PMID 39994346 doi:10.1038/s42003-025-07738-0
7. Han X, Yuan T, Zhang J, et al.. FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway Journal of cellular and molecular medicine; 2022. PMID 35510614 doi:10.1111/jcmm.17333

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.