FOXO4-DRI Research: What Published Studies Have Investigated

What is FOXO4-DRI?

What is FOXO4-DRI? It is a synthetic peptide designed to interfere with a specific protein–protein interaction: the one between the transcription factor FOXO4 and the tumour suppressor p53. The “DRI” in the name is a chemistry description, not a brand: D-amino acid retro-inverso. The peptide is built from D-amino acids rather than the natural L forms, with the sequence order reversed.

Why retro-inverso

A retro-inverso peptide is a standard trick in peptide chemistry with a specific purpose. Proteases recognise L-amino-acid backbones; a chain of D-amino acids is largely invisible to them, so it survives far longer. Reversing the sequence order at the same time approximately restores the spatial arrangement of the side chains, so the mirrored chain can present a similar surface to a binding partner while resisting degradation. It is a way of buying stability without redesigning the interaction from scratch.

Bourgeois and colleagues (2025, Nat Commun, PMID 40593617) describe the construct as containing two functional parts: a FOXO4-derived region and a cationic cell-permeability peptide, the latter needed because a peptide targeting an intracellular interaction has to get inside the cell first. Notably, they report that both parts contribute to the interaction with p53 — the cell-penetrating segment is not merely a delivery tag.

Discovery and origin in the literature

The 2017 Cell paper

Baar and colleagues published the founding work in Cell in March 2017 (PMID 28340339), from de Keizer’s group at Erasmus MC with collaborators in Graz and at the Buck Institute. Their reasoning, as stated in the paper, was to identify how senescent cells avoid apoptosis and then design a compound against that mechanism. They identified FOXO4 as a pivot in senescent-cell viability, designed a FOXO4 peptide that perturbs FOXO4’s interaction with p53, and reported that in senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis.

The in-vivo results are what made the paper famous. The authors reported that, in their words, “under conditions where it was well tolerated in vivo”, the peptide neutralised doxorubicin-induced chemotoxicity, and that it restored fitness, fur density and renal function in both fast-ageing XpdTTD/TTD mice and naturally aged mice. Those three endpoints — one behavioural, one visible, one biochemical — are why this result travelled far beyond the senescence literature.

The conditional clause in that sentence is part of the finding, not decoration. The authors chose to state that the effects were obtained under conditions where the compound was well tolerated, which is a scientist’s way of noting that tolerability was a live variable in the experiments. Secondary accounts almost universally drop it.

The 2025 structural follow-up

Eight years later, Bourgeois and colleagues (2025) reported solution-NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain, and in complex with FOXO4-DRI. Their finding is chemically interesting: two disordered regions — a disordered FOXO4-DRI and the disordered p53TAD2 — form what they describe as a transiently folded complex. They also report that phosphorylation of p53 enhances affinity for both FOXO4 and FOXO4-DRI. This is the first structural characterisation of the interaction the 2017 peptide was designed around, arriving well after the compound entered popular circulation.

The disclosures on that paper belong on the record. The research was partly funded by Cleara Biotech; de Keizer and Madl hold shares in that company; and several authors hold published patents covering compounds that bind p53 and inhibit the FOXO4–p53 interaction. Again: a disclosure is not a disqualification. It is context a reader is entitled to have.

Reference data

The molecule facts below are drawn from the public chemical record (PubChem CID 167312269). The full residue sequence is not reproduced here because we could not verify a canonical published string to the standard this site applies to sequences; the structural description above is what the primary literature states.

At roughly 5358 Da this is a large peptide by the standards of this catalogue — several times the mass of most compounds documented here — which has consequences for synthesis quality discussed further below. No reconstitution procedure, quantity or route is given or implied on this page.

Mechanisms researchers have examined

• Disruption of the FOXO4–p53 interaction — the design premise. Baar and colleagues (2017) identified FOXO4 as a factor in senescent-cell viability and built the peptide to perturb its association with p53.
• p53 nuclear exclusion — the reported proximate consequence in senescent cells, followed by cell-intrinsic apoptosis in the systems studied. Kong and colleagues (2025, Commun Biol, PMID 39994346) reported a related account in keloid senescent fibroblasts, framed around nuclear exclusion of upregulated p53 serine-15 phosphorylation.
• Binding to a disordered region — Bourgeois and colleagues (2025) report that the target is the disordered p53 transactivation domain and that the complex formed is transient rather than a stable fold. Targeting intrinsically disordered regions is a difficult problem in drug design, and this is one of the better-characterised examples.
• Phosphorylation-dependent affinity — the same paper reports that p53 phosphorylation enhances affinity for both FOXO4 and FOXO4-DRI, which offers a possible account of selectivity for senescent cells, where p53 phosphorylation states differ.
• Protease resistance from D-amino-acid chemistry — a property of the construct rather than a biological mechanism, but the reason the molecule can be studied in vivo at all.

Each point names a mechanism examined in a defined system, not an effect in a reader.

Research areas in the literature

Ageing and chemotoxicity models in mice

The 2017 paper remains the whole of this category: XpdTTD/TTD fast-ageing mice, naturally aged mice, and a doxorubicin chemotoxicity model, with fitness, fur density and renal-function endpoints.

Cell-culture applications by independent groups

Huang and colleagues (2021, Front Bioeng Biotechnol, PMID 33996787) reported that FOXO4-DRI selectively removed senescent cells from in-vitro expanded human chondrocytes — a tissue-engineering application, where the goal is a cleaner cell population in a dish rather than any effect in an organism. This is arguably the use case with the least distance between the published result and the actual application.

Fibrosis models

Han and colleagues (2022, J Cell Mol Med, PMID 35510614) reported that a FOXO4 peptide targeting myofibroblasts ameliorated bleomycin-induced pulmonary fibrosis in mice, attributing the effect to an ECM-receptor interaction pathway.

The result that points the other way

Born and colleagues (2023, Circulation, PMID 36515093) investigated senescent cells in pulmonary hypertension, using several independent means of clearing them: a genetic suicide construct in p16-ATTAC mice, the senolytic ABT263, and FOXO4-DRI. What they reported is the opposite of the expected direction. Senescent-cell elimination increased right-ventricular systolic pressure and the hypertrophy index, increased vessel remodelling, and markedly decreased lung pulmonary endothelial cells. Mice given either ABT263 or FOXO4-DRI showed pulmonary haemodynamic alterations and endothelial-cell loss relative to controls, and in monocrotaline-treated rats an early modest benefit from ABT263 was aggravated by three weeks. The authors’ stated conclusion was that elimination of senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary haemodynamics, and that this invites consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence.

That paper is cited here at length deliberately. It is in a major cardiovascular journal, it used three independent clearance methods including this compound, and it is almost entirely absent from the popular writing about FOXO4-DRI.

Research models and evidence status

This section carries more weight on this page than on any other in the library, because FOXO4-DRI is the compound in this catalogue whose public reputation is furthest ahead of its published evidence.

What is not established — the short version

• There is no human data. None. A ClinicalTrials.gov search returns no registered study of FOXO4-DRI. There is no published phase 1, no human pharmacokinetics, no human safety or tolerability record, and no dose-finding work in people. Nine years after the founding paper, that absence is itself informative.
• The headline mouse result is a single study. The 2017 Cell paper has not, as far as we could determine, been independently replicated in its ageing endpoints by an unaffiliated laboratory.
• Tolerability was a stated condition of the result. The authors themselves qualified the in-vivo findings as obtained under conditions where the compound was well tolerated. A compound that requires a tolerability window to be found is a compound with a tolerability question.
• Clearing senescent cells is not uniformly beneficial. Born and colleagues (2023) reported the opposite direction in pulmonary models with three independent clearance methods. Senescent cells have physiological roles, and removing them is a perturbation with more than one possible sign.
• The structural basis arrived in 2025, not 2017. For eight years the compound circulated with no published structure of the interaction it was built to disrupt.
• The field has commercial entanglement. Cleara Biotech funding, shareholdings and patents are disclosed on the 2025 paper by authors of the founding work.

Why the online framing outruns all of this

“Removes aged cells and restored fur and kidney function in old mice” is a compressible sentence. “Single unreplicated study, tolerability-conditional, no human data, and one paper reporting harm in a different model” is not. The compression is where the exaggeration comes from, and it is why the word senolytic does most of the marketing work around this molecule while doing very little descriptive work. Senolytic describes a mechanism a compound was designed to have, not an outcome anyone has demonstrated in a person.

Nothing in this literature establishes any property of the supplied research material in a person. This page makes no efficacy, therapeutic, senolytic, anti-ageing, longevity, cosmetic or other use claim of any kind, and the material is supplied for laboratory research use only — not for human or veterinary use. Where it is genuinely useful is stated above: as a tool compound in cell culture and animal models of senescence, which is what every paper cited here actually used it as.

How to verify this compound yourself

FOXO4-DRI is the hardest synthesis in this article set, and its certificate of analysis carries correspondingly more weight:

• HPLC purity, on a long chain — at ≈ 5358 Da this is a long peptide. Solid-phase synthesis accumulates deletion sequences with chain length, so a long, highly cationic construct produces a messier crude product than a short one and the purity figure is doing real work. A low or absent HPLC number on a peptide this size is a serious gap.
• Mass-spec identity — confirms measured mass against the expected ≈ 5358 Da. This also distinguishes the full construct from truncated species that would retain some of the sequence but not the functional architecture.
• The stereochemistry question that no routine COA answers — the defining feature of this compound is that its residues are D-amino acids in reversed order. Standard HPLC purity and mass spectrometry cannot distinguish a D-peptide from its L-enantiomer: they have identical mass and, on an achiral column, near-identical retention. Establishing the retro-inverso chemistry requires chiral analysis, which is not part of a routine certificate. That is a genuine limitation of the standard paperwork for this specific molecule and it is worth knowing rather than assuming away.
• Counter-ion and net peptide content — a heavily cationic construct is isolated as a salt, commonly trifluoroacetate, and the counter-ion contributes meaningfully to the weighed mass of a peptide this size.
• Endotoxin — relevant wherever the material is used in cell-viability or apoptosis assays. Reported in EU/mL where tested, independent of chemical purity.

See how to read a COA for what each certificate line means, and how to verify peptide purity for how the methods fit together. The exact batch received can be checked on the self-serve verify tool.

Research-grade sourcing and verification

FOXO4-DRI is not held in stock. It is listed on our sourcing catalogue as available to order — our supplier lists it, we have not bought it, and material of this kind typically takes about two to three weeks to reach us. For laboratory research use only, it is supplied with a per-batch Certificate of Analysis reporting HPLC purity (%) and mass-spec identity confirmation, verifiable at the lot level. For adjacent compounds in this library whose literature is likewise dominated by ageing-research framing, see Epitalon research and humanin research — both documented with the same honesty about what has and has not been shown. This is sourcing and quality-assurance framing only.

Frequently asked questions

Literature cited

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;169(1):132–147.e16. PMID 28340339. pubmed.ncbi.nlm.nih.gov/28340339. The founding paper; results stated as obtained under conditions where the peptide was well tolerated in vivo.
2. Huang Y, He Y, Makarcyzk MJ, Lin H. “Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.” Front Bioeng Biotechnol. 2021;9:677576. PMID 33996787. pubmed.ncbi.nlm.nih.gov/33996787.
3. Han X, Yuan T, Zhang J, et al. “FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway.” J Cell Mol Med. 2022;26(11):3269–3280. PMID 35510614. pubmed.ncbi.nlm.nih.gov/35510614.
4. Born E, Lipskaia L, Breau M, et al. “Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.” Circulation. 2023;147(8):650–666. PMID 36515093. pubmed.ncbi.nlm.nih.gov/36515093. Reported that senolytic interventions, including FOXO4-DRI, may worsen pulmonary haemodynamics.
5. 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.” Commun Biol. 2025;8(1):299. PMID 39994346. pubmed.ncbi.nlm.nih.gov/39994346.
6. 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.” Nat Commun. 2025;16(1):5672. PMID 40593617. pubmed.ncbi.nlm.nih.gov/40593617. Authors disclose Cleara Biotech funding, shareholdings and related patents.
7. National Center for Biotechnology Information. “PubChem Compound Summary for CID 167312269, FOXO4-DRI.” pubchem.ncbi.nlm.nih.gov/compound/167312269 (formula, mass, CAS 2460055-10-9).