FOXO4-DRI
LongevityResearch Use OnlyLast reviewed: September 28, 2026
Quick Facts
- What it is
- A synthetic D-retro-inverso peptide built from the FOXO4 sequence — a senolytic, designed to disrupt the FOXO4–p53 interaction and kill senescent cells selectively.
- How it's taken
- Not established in humans — every published route is an experimental route in mice
- Half-life
- Not characterized in humans — the retro-inverso design is intended to resist protease degradation, but no human pharmacokinetic data exist
- Typical research dose
- No human dose exists — published regimens are mouse protocols and do not convert by arithmetic
- Research status
- Preclinical only. No approval anywhere, and no human study of any design was located.
On this page
Where to source FOXO4-DRI
FOXO4-DRI has no approved medical use and is sold by specialty research peptide vendors as material for laboratory use only. It is a long peptide and correspondingly expensive to synthesise, which makes purity verification more than a formality — a Certificate of Analysis is the only identity and purity check available to a buyer.
Batch-traceable COAs · cold-chain shipping
Public COAs · vendor-stated 99%+
Bioviridian-tested · verifiable COAs
Also stocking FOXO4-DRI
Peptide Giants, Peptides.gg, BioLongevity Labs — each carries a current price row for this compound.
What is FOXO4-DRI?
FOXO4-DRI is a synthetic peptide derived from the FOXO4 transcription factor and built in a D-retro-inverso configuration — D-amino acids assembled in reverse order, a design intended to survive the proteases that would destroy an ordinary peptide. It belongs to a compound class called senolytics, whose defining idea is selective killing: senescent cells stop dividing but refuse to die, accumulate with age and after chemotherapy, and are thought to degrade the tissue around them. FOXO4-DRI was engineered to remove them.
There is no human data on this compound. No clinical trial, no observational study, no published case report. The whole evidence base is mice and cells in culture, and has been since the peptide was described in Cell in 2017. That is not a caveat at the end of the page; it is the frame for everything on it. New to peptide research? Start with the basics
Reported in the cited studies: selective apoptosis of senescent cells through p53 nuclear exclusion [1]; neutralisation of doxorubicin-induced chemotoxicity and restored fitness, fur density and renal function in fast-aging and naturally aged mice [1]; improved age-related testosterone secretion in aged mice [2]; selective removal of senescent cells from cultured human chondrocytes [3]; and reduced fibrosis in a mouse model of bleomycin-induced lung injury [4].
The library's other Longevity entries include Epitalon and SS-31.
How does FOXO4-DRI work?
The mechanism is unusually well specified for a research peptide, and it has been retested by more than one group. What it has not been is tested in a person.
- The senescent-cell survival problem [1]. Senescent cells stop dividing but resist apoptosis, and they accumulate with age and after chemotherapy. FOXO4 was identified as a pivot in that resistance: it holds p53 in the nucleus in a configuration that keeps the senescent cell alive (Baar et al. 2017).
- Disrupting FOXO4-p53 [1]. The peptide was designed to perturb that interaction. In senescent cells it causes p53 to be excluded from the nucleus, which triggers cell-intrinsic apoptosis. Non-senescent cells are reported to be largely unaffected, which is the basis of the selectivity claim.
- The retro-inverso design. D-amino acids in reversed sequence give a peptide that presents a similar side-chain topology to the natural L-peptide while resisting the proteases that would degrade it. This is a stability design choice, not a separate mechanism.
- Independent mechanistic retest [5]. Work on keloid fibroblasts reports the same nuclear-exclusion mechanism, driven by p53 phosphorylated at serine 15 (Kong et al. 2025) — the 2017 account holding up in a different cell type and a different laboratory.
What is FOXO4-DRI researched for?
The research divides into the aging work it was designed for and a set of extensions into fibrotic and age-related tissue disease. Every study below is a mouse study or a cell-culture study. The order here runs from the strongest design to the weakest.
- Aging and chemotoxicity in mice [1]. The originating study reported neutralisation of doxorubicin-induced chemotoxicity, and restoration of fitness, fur density and renal function in fast-aging XpdTTD/TTD mice and naturally aged mice (Baar et al. 2017).
- Age-related testosterone insufficiency in aged mice [2]. An independent group reported that targeting senescent Leydig cells with FOXO4-DRI alleviated age-related insufficiency of testosterone secretion in aged mice (Zhang et al. 2020).
- Human chondrocytes in culture [3]. FOXO4-DRI selectively removed senescent cells from in-vitro expanded human chondrocytes, a result relevant to cartilage tissue engineering (Huang et al. 2021). Human cells, not a human subject.
- Pulmonary fibrosis in mice [4]. In a bleomycin-induced model, the peptide reduced fibroblast extracellular-matrix production and lessened fibrosis (Liu et al. 2023).
- Keloid fibroblasts [5]. Apoptosis of senescent keloid fibroblasts via p53 nuclear exclusion (Kong et al. 2025). Cell-level work.
- No human data of any kind. Prof. Peptide located no clinical trial, no observational study and no published case report involving FOXO4-DRI in humans.
How is FOXO4-DRI dosed, and what is known about safety?
There is no human dose for FOXO4-DRI, and the safety information is reported in the same section because both answers come from the same place: animal experiments. Separating them would imply a human safety record that does not exist.
Every published regimen is an animal regimen. The originating study administered the peptide to mice under an experimental protocol and described it as well tolerated under the conditions tested [1]; the later mouse studies each used their own protocols [2][4]. Milligram-per-kilogram figures from a mouse do not convert to a human schedule by arithmetic — species differ in clearance, distribution and tolerance, and a senolytic's whole premise is selective killing of a cell population, which is not a margin where extrapolation is safe. Prof. Peptide therefore publishes no dose, no frequency and no route for this compound. On safety, the position follows directly: there is no human safety data, no adverse-event record in people, no interaction data and no long-term follow-up, because no person has been studied taking it in any report located here. The tolerability statements in the literature are statements about mice in short experiments. A compound whose intended action is to induce apoptosis warrants that distinction being made explicitly rather than assumed. Research vendors sell FOXO4-DRI as lyophilised material labelled for laboratory use only; a Certificate of Analysis is the only identity and purity check available to a buyer.
What are the limitations of FOXO4-DRI research?
There is no human data. Not limited human data, not preliminary human data — none. Everything published about this compound comes from mice and from cells in culture, and that has been true for the eight years since the compound was described.
The preclinical work itself is comparatively strong, which is what makes the gap worth stating carefully rather than dismissively. The originating paper is in Cell, the mechanism has been retested by unconnected groups in different tissues, and the selectivity claim has been reproduced in cultured human cells. That is a good preclinical record. It is also the stage at which a large majority of compounds fail, and senolytics as a class have no approved member.
The mouse aging results rest partly on a progeroid model — XpdTTD/TTD mice, which age prematurely through a specific DNA-repair defect. Reversing features of accelerated aging in such a model is not the same finding as extending healthspan in a normally aging organism, and the paper reports both separately for that reason.
No pharmacokinetics in humans, no dose-finding, no safety margin, and no regulatory review anywhere. FOXO4-DRI is research-use-only material.
FOXO4-DRI FAQ
What is FOXO4-DRI?
FOXO4-DRI is a synthetic peptide built from the FOXO4 transcription-factor sequence in a D-retro-inverso configuration — D-amino acids in reversed order, a design used to resist protease degradation. It was created to interfere with the interaction between FOXO4 and the tumour-suppressor protein p53, and it is studied as a senolytic: a compound intended to kill senescent cells rather than to act on healthy ones.
Has FOXO4-DRI been tested in humans?
No. Prof. Peptide located no human study of FOXO4-DRI — no clinical trial, no observational report, no case series. The entire published evidence base is preclinical: mouse experiments and cell-culture work, including work on cultured human cells. That is the single most important fact on this page, and it has not changed since the compound was first described in 2017.
What did the original 2017 study show?
Baar and colleagues, publishing in Cell, identified FOXO4 as a pivot in senescent-cell survival and designed a FOXO4 peptide that disrupts its interaction with p53. In senescent cells this caused p53 to be excluded from the nucleus and triggered cell-intrinsic apoptosis. In mice, under conditions the authors describe as well tolerated, the peptide neutralised doxorubicin-induced chemotoxicity and restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice. Those are mouse outcomes.
Is FOXO4-DRI FDA-approved?
No. FOXO4-DRI is not approved by the FDA or any comparable regulator for any indication, and it has no approved medical use anywhere Prof. Peptide could identify. It is sold as research-use-only material by specialty peptide vendors.
Is there a standard FOXO4-DRI dose?
No human dose exists, because no human study exists. The published regimens are mouse regimens, expressed per kilogram of mouse body weight in specific experimental protocols, and they do not translate to a human schedule by arithmetic. Prof. Peptide publishes no dosing figure for this compound.
References
- 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. doi:10.1016/j.cell.2017.02.031. PMID 28340339. https://pubmed.ncbi.nlm.nih.gov/28340339/
- 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 (Albany NY). 2020;12(2):1272-1284. doi:10.18632/aging.102682. PMID 31959736. https://pubmed.ncbi.nlm.nih.gov/31959736/
- Huang Y, He Y, Makarcyzk MJ, et al. Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Front Bioeng Biotechnol. 2021;9:677576. doi:10.3389/fbioe.2021.677576. PMID 33996787. https://pubmed.ncbi.nlm.nih.gov/33996787/
- Liu Y, Hou Q, Wang R, et al. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(10):2393-2403. doi:10.1007/s00210-023-02452-2. PMID 37074394. https://pubmed.ncbi.nlm.nih.gov/37074394/
- 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. doi:10.1038/s42003-025-07738-0. PMID 39994346. https://pubmed.ncbi.nlm.nih.gov/39994346/
Published Studies
Plain-English summaries of the peer-reviewed studies behind the statements above. Click any title to read the source paper. Every one of them is a mouse study or a cell-culture study.
Baar MP, Brandt RMC, Putavet DA, et al.; de Keizer PLJ.
The paper that created the compound, and still the reference point for everything else about it. The authors identified FOXO4 as a pivot in senescent-cell viability and designed a FOXO4 peptide that perturbs the FOXO4-p53 interaction. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. In vivo, under conditions the paper describes as well tolerated, it neutralised doxorubicin-induced chemotoxicity and restored fitness, fur density and renal function in fast-aging XpdTTD/TTD mice and in naturally aged mice. All in-vivo work is in mice.
Zhang C, Xie Y, Chen H, et al.
An independent group in Guangzhou applied FOXO4-DRI to late-onset hypogonadism in aged mice, on the rationale that the core mechanism is dysfunction of senescent Leydig cells. The paper reports that FOXO4 is expressed in human Leydig cells and that targeting senescent Leydig cells in aged mice alleviated age-related insufficiency of testosterone secretion. Independent replication of the senolytic mechanism in a different tissue — and still a mouse study.
Huang Y, He Y, Makarcyzk MJ, et al.
Cell-culture work on human cells, which is a different thing from a human study. Chondrocytes expanded in vitro accumulate senescent cells, which limits their use in cartilage engineering; the authors report that FOXO4-DRI selectively removed those senescent cells from the expanded population. The result supports the selectivity claim in human cells. It says nothing about what happens in a person.
Liu Y, Hou Q, Wang R, et al.
A mouse model of pulmonary fibrosis induced with bleomycin, reporting that FOXO4-DRI reduced extracellular matrix production in fibroblasts and lessened the fibrotic response. One of several papers extending the peptide beyond the aging context into fibrotic disease models — again, entirely in mice and cultured cells.
Kong YX, Li ZS, Liu YB, et al.
The most recent work located here, applying the peptide to keloid fibroblasts and reporting apoptosis driven by nuclear exclusion of p53 phosphorylated at serine 15. It is useful mainly because it retests the mechanism the 2017 paper proposed, in a different cell type, and finds it — the mechanistic account has held up across groups. It remains cell-level work.
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