FOXO4-DRI: research, side effects and dosage in studies

In short

FOXO4-DRI is a peptide designed for research that kills senescent cells. In mice it improved signs of ageing [1]C, but it has not been studied in humans and has no marketing authorisation in any EU or EEA country [16] [23]regulator.

• There are no human studies. All the evidence is from cells and animals, and the substance has not been clinically validated [16].
• In the original 2017 study, the mice's fitness, fur and kidney function improved [1]C. Lifespan was not measured.
• Later mouse studies report benefits in lung fibrosis and in testosterone secretion in old mice [3, 7, 8]C.
• Counter-evidence: in animal models of pulmonary hypertension, removing senescent cells, including with FOXO4-DRI, made the disease worse [9]C.
• It is not named in Annex 1 A of Fimea's medicines list [21]regulator. WADA's class S0 bans substances without approval by any regulatory authority [24]regulator.

What is FOXO4-DRI?

FOXO4-DRI is a synthetic peptide described by a Dutch research group in 2017. It mimics part of the FOXO4 protein and disturbs the binding between FOXO4 and the p53 protein [1]C.

The abbreviation DRI means the peptide is built from D-form amino acids in reversed order. According to the researchers, such a form can change a peptide's chemical properties and potency [1]D. A structural study found that the peptide binds to the flexible, unstructured part of p53 [12]D.

FOXO4-DRI belongs to the senolytics, substances that remove senescent cells. Other senolytic classes studied include Bcl-2 family inhibitors, HSP90 inhibitors and the combination of dasatinib and quercetin [26]D. Basics: What are peptides?. All substances: Peptides A-Z.

Evidence at a glance

Each cell gives the kind of study and its source. The letter is the evidence level, not the result.

"-" = no such study is known.

What is FOXO4-DRI studied for?

FOXO4-DRI is studied in cell and animal models where senescent cells are thought to make a disease worse. None of this has been studied in humans [16].

• Ageing and the harms of chemotherapy: fast-ageing and naturally old mice, and mice exposed to doxorubicin [1]C.
• Lungs: lung fibrosis in mice [7, 8]C, fibrosis after radiotherapy in animal studies [6]C and a rat model of a lung disease of premature babies [10]C.
• Male hormones: testosterone secretion and sperm production in old mice [3, 4]C.
• Blood vessels: ageing of the aorta in mice [13]C.
• Alongside cancer treatment: strengthening radiotherapy for lung cancer in animal studies [6]C and glioblastoma cells [14]D.
• Cartilage and scars: human cartilage cells in culture [5]D and keloid scar tissue [11]D.

According to a 2026 review, FOXO4-DRI has shown senolytic activity in preclinical models but has not been clinically validated [16].

How does FOXO4-DRI work?

In senescent cells FOXO4-DRI detaches the p53 protein from FOXO4, p53 then moves out of the nucleus, and the cell dies in a programmed way [1]D.

Senescent cells no longer divide, but they resist cell death. According to the original study, FOXO4 keeps p53 tied to structures in the nucleus and so prevents cell death [1]D. In cell culture, FOXO4-DRI reduced the viability of senescent human connective tissue cells far more than that of ordinary cells [1]D.

Later studies describe the same route, for example in blood vessel lining cells [13]C and in keloid scar cells [11]D. All mechanistic data come from cell and animal studies.

Has FOXO4-DRI been studied in humans?

No. There are no published human studies, and no registered clinical trials are known (October 2026) [16].

The closest to humans are experiments on human cells and tissue: cultured cartilage cells [5]D, keloid scar tissue taken from patients [11]D and human connective tissue cells [1]D. These are laboratory experiments, not treatment studies.

A review on brain ageing states that in humans only other substances linked to the same pathway, such as fisetin, have been studied, not FOXO4-DRI [15].

Promising, but only in animal and cell studies

All findings on FOXO4-DRI come from animal and cell studies, and none has been tested in humans [16].

• Ageing mice no human studies

  In the original study, fitness, fur density and kidney values improved in fast-ageing and naturally old mice, and in mice exposed to doxorubicin the liver values and weight loss were corrected [1]C. The groups were small, 7-8 mice per group in the kidney measurement, and follow-up lasted about a month. Lifespan was not measured [1]C.

  If it held in humans: removing senescent cells could affect some age-related changes, such as kidney function.

  Why it might not translate: the groups were small, follow-up lasted about a month and lifespan was not measured. The fast-ageing mouse strain does not match human ageing, and the mice received the substance directly into the bloodstream or the abdominal cavity.

  Evidence now: one original study [1]C; no human study has been published or registered [16].

• Lung scarring no human studies

  In two Chinese mouse studies, scarring and collagen build-up caused by bleomycin stayed lower [7, 8]C, and in one study lung fibrosis after radiotherapy was reduced [6]C. The bleomycin model develops in days, while human lung fibrosis takes years.

  If it held in humans: the substance could reduce lung scarring.

  Why it might not translate: the bleomycin model develops in days, while human lung fibrosis takes years. The radiotherapy model has been studied in one experiment.

  Evidence now: three mouse studies [6, 7, 8]C; no human study.

• Hormone function in old mice no human studies

  In two studies from the same Chinese group, senescent Leydig cells were removed, testosterone secretion increased and sperm quality improved [3, 4]C. The results have not been repeated by other groups.

  If it held in humans: the substance could affect testosterone production in ageing testes.

  Why it might not translate: both studies come from the same group and the results have not been repeated elsewhere. Ageing of the mouse testis may not match that of humans.

  Evidence now: two studies by the same group in mice and cells [3, 4]C; the substance has not been given to humans.

• Blood vessels no human studies

  In old and prematurely ageing mice, the function of the aorta improved [13]C.

  If it held in humans: the substance could affect the ageing of arteries.

  Why it might not translate: this is a single mouse study and the result has not been repeated.

  Evidence now: one mouse study [13]C; no human study.

• Cells of human origin no human studies

  More than half of the long-expanded cultured cartilage cells were removed, but cartilage formation did not improve [5]D. Cell death was seen in keloid scar cells [11]D.

  If it held in humans: the substance could also remove senescent cells from human tissue.

  Why it might not translate: a culture does not match living tissue, and in the cartilage cells the removal of cells did not improve cartilage formation.

  Evidence now: two laboratory studies [5, 11]D; no human study.

Who studies FOXO4-DRI?

FOXO4-DRI was described by a research group at Erasmus MC in Rotterdam together with the University of Graz and the Buck Institute in the United States [1]C.

• The original group: Rotterdam and Graz continued with structural work in 2025. According to the publication, part of the funding came from a company, and two authors hold shares in it and are named on related patents [12]D.
• Chinese groups: most of the later animal studies were done in China [3, 4, 7, 8, 11, 13]C.
• Others: the University of Pittsburgh studied cartilage cells [5]D, a French group pulmonary hypertension [9]C and a US group a model of a lung disease of premature babies [10]C. Competing peptides for the same target have been designed in Oregon and South Korea [17]C [18]D.

Who wrote this page: the editorial team

This page was written by the Molecular Recovery editors. The draft was made with the help of AI, and the claims were checked against the sources (AI policy). The page has not been medically reviewed. How we work: About us.

What is the half-life of FOXO4-DRI?

There are no data from humans: the half-life of FOXO4-DRI in people is unpublished, and so are its levels in human blood.

In cell culture the peptide was detectable inside cells 2-4 hours after it was added and still after at least 72 hours [1]D. In the mouse studies it was given straight into the bloodstream or into the abdominal cavity [1]C.

What side effects does FOXO4-DRI have?

There are no harm data from humans, because there are no human studies [16]. On peptide side effects more broadly: side effects in studies.

What animal and cell studies tell us

According to the original study, the mice tolerated the substance well under the conditions used, and in cell culture the effect fell far more heavily on senescent cells than on ordinary ones [1]C. The experiments lasted days or weeks, so there are no data on long-term effects.

According to a review, interfering with p53 requires a separate assessment of how it affects the body's own surveillance against cancer, as well as long-term toxicology [16].

A harmful result in an animal model

In a study of pulmonary hypertension, removing senescent cells with FOXO4-DRI or a Bcl-2 inhibitor raised right ventricular pressure, increased vessel remodelling and reduced lung vessel lining cells. The researchers warn that senolytic treatments may worsen pulmonary circulation [9]C.

Product quality as a risk of its own

With injectable peptides bought online, contamination and wrong contents are risks, and Fimea warns against using them [20]regulator.

Interactions and who has no data

There is no human-level research on interactions with medicines. There are no data on pregnancy, breastfeeding, children or people with long-term illnesses.

In animal studies FOXO4-DRI has been given together with a chemotherapy drug or radiotherapy, and in those models it reduced the harms of the treatment or strengthened it [1, 6]C. These are animal models, not treatment recommendations, and in another model senolytic treatment made the disease worse [9]C.

What speaks against it and what is unknown

There is no human evidence for FOXO4-DRI, and the animal studies include a harmful result [9]C [16].

Counter-evidence

• In animal models of pulmonary hypertension, removing senescent cells, including with FOXO4-DRI, made the disease worse and reduced lung vessel lining cells [9]C.
• In human cartilage cells the substance removed senescent cells but did not improve the ability to produce cartilage [5]D.
• In a computational comparison another peptide, ES2, was rated more effective than the FOXO4-based peptide [17]C.
• According to a review, FOXO4's part in many frequently cited effects is inferred from other FOXO family members rather than measured directly [16].

What the evidence does not support

• "FOXO4-DRI rejuvenates people": there are no human studies [16].
• "FOXO4-DRI extends lifespan": the original study measured function and organ performance, not lifespan [1]C.
• "A senolytic is always safe because it only removes damaged cells": in an animal model the removal made pulmonary hypertension worse [9]C.
• "The substance has been clinically studied": according to a review, clinical validation is missing [16].

It is not known how the substance behaves in the human body, what long-term use would do, or how interfering with p53 affects cancer risk [16].

FOXO4-DRI dosage in studies

There are no doses studied in humans, so there is no dose page. FOXO4-DRI has no approved dosage and no published human dose. The figures below are animal doses and cell-culture conditions, not recommendations.

What the numbers do not tell you. An amount given to a mouse per kilogram of body weight is not converted into a human dose by weight, and both routes used in the mouse studies are research conditions. Because there are no human studies, no safe or effective human dose is known. On reading study doses more generally: dosage in studies.

FOXO4-DRI and other senolytics: what is the difference?

FOXO4-DRI is a peptide, whereas the best-known senolytics are small molecules. None of them is approved for treating ageing.

• Bcl-2 inhibitors (ABT-263, ABT-737): according to the original study, ABT-737 also affected ordinary cells at low concentrations, while FOXO4-DRI kept its selectivity [1]D. A review names a fall in platelets as the problem with Bcl-2 inhibitors [19].
• Dasatinib and quercetin and HSP90 inhibitors: these are used as comparison substances in senolytic research [26]D.
• Newer peptides: ES2, designed in Oregon, and CPP-CAND from South Korea aim at the same FOXO4-p53 target [17]C [18]D.

Among the other ageing-related substances on this site, epitalon and NAD+ are studied through different mechanisms. Removing senescent cells is a separate approach [16].

Combinations and blends

As far as we know, FOXO4-DRI is not sold in the blends covered on this site, and there is no published study on combining it with other peptides.

In animal studies it has been used together with cancer treatments [1, 6]C and compared with a Bcl-2 inhibitor in the same experiment [9]C. On blends in general: blends.

Is FOXO4-DRI legal in Finland?

FOXO4-DRI has no marketing authorisation in Finland or elsewhere in the EU or EEA [23]regulator, so it may not be sold or marketed as a medicine. It is not named in Annex 1 A of Fimea's medicines list [21]regulator.

• Medicines list. Annex 1 A of the Finnish medicines list (230/2025) covers medicine analogues and prohormones classified as medicines, but FOXO4-DRI is not on the list [21]regulator. Fimea can still classify an individual product as a medicine; classification is done product by product based on composition and intended use [25]regulator.
• Marketing authorisation. EMA's data on centrally authorised medicines did not include FOXO4-DRI on 14 Oct 2026 [22]regulator, and EMA's Article 57 database showed it in no EU or EEA country (data as of 9 Oct 2026) [23]regulator.
• Fimea's warning of 29 Jun 2026. Fimea warned against injectable peptides bought online. The label "for research use only" means the product is not intended for humans [20]regulator.
• Import. Ordering medicines from outside the EU is covered on the page Peptides and the law in Finland. Bringing them back from travel: Travelling with peptides.

This is not legal advice. Disclaimer.

Is FOXO4-DRI a doping substance?

FOXO4-DRI is not named on the Prohibited List. Class S0 of WADA's 2026 list bans at all times any pharmacological substance not covered by the other classes and without approval by any regulatory health authority for human therapeutic use; the class explicitly mentions drugs under preclinical or clinical development [24]regulator. FOXO4-DRI has no marketing authorisation in EU or EEA countries [23]regulator. Athletes should check with the Finnish Center for Integrity in Sports (SUEK).

How should a FOXO4-DRI product be assessed?

There is no way to be sure what a product contains. We know of no published laboratory analyses of FOXO4-DRI products on sale, and according to Fimea an unauthorised product may contain a different substance from what the package says [20]regulator.

FOXO4-DRI is more complex than ordinary research peptides: it contains D-form amino acids in reversed order and a separate segment that crosses the cell membrane [1]D. A purity percentage alone does not show whether the structure is right. A certificate of analysis (COA) should include HPLC for purity and mass spectrometry for identity. More: How to read a COA. On handling: Mixing and handling.

The future: what comes next?

No registered human trials are known (October 2026). According to a 2026 review, clinical use still requires tissue-specific validation, studies of pharmacokinetics and delivery, long-term toxicology and an assessment of the effect on the body's own cancer surveillance [16].

Research is also moving on to the next peptides: ES2 and CPP-CAND were designed for the same target [17]C [18]D. The 2025 structural study provides a basis for new molecules [12]D.

FAQ

Read the research yourself: sources

Every source opens the original publication or the regulator's page. The level shows what the source itself reports.

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 C
2. Krimpenfort P, Berns A. Rejuvenation by therapeutic elimination of senescent cells. Cell. 2017;169(1):3-5. PMID 28340347 (review)
3. 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. PMID 31959736 C
4. Li Y, Zhang C, Cheng H, et al. FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells. Exp Gerontol. 2024;195:112522. PMID 39025385 C
5. 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 D
6. Meng J, Li Y, Wan C, et al. Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis. JCI Insight. 2021;6(23):e146334. PMID 34877934 C
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. J Cell Mol Med. 2022;26(11):3269-3280. PMID 35510614 C
8. Liu Y, Hou Q, Wang R, et al. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(10):2393-2403. PMID 37074394 C
9. 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 C
10. Jing X, Jia S, Teng M, et al. Cellular senescence contributes to the progression of hyperoxic bronchopulmonary dysplasia. Am J Respir Cell Mol Biol. 2024;70(2):94-109. PMID 37874230 C
11. 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 D
12. 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 D
13. Hu Z, Li F, Hu C, et al. FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway. Front Bioeng Biotechnol. 2025;13:1729166. PMID 41625068 C
14. Ning N, Wang C, Gao T, et al. Acylglycerol kinase sensitizes glioblastoma to temozolomide via limiting mitochondrial damage related cellular senescence. Mol Carcinog. 2026;65(9):1092-1104. PMID 42391447 D
15. Alameen AAM, Al-Kuraishy HM, Fawzy MN, Batiha GE. Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain aging and cognitive decline. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(10):14659-14676. PMID 42024235 (review)
16. Mateescu DM, Gavrilescu DM, Marinescu AR, et al. FOXO4 as a redox-sensitive regulator of antioxidant defense and cellular senescence: cysteine-based signaling, p53 interaction, and therapeutic targeting. Antioxidants (Basel). 2026;15(7):842. PMID 42510573 (review)
17. Le HH, Cinaroglu SS, Manalo EC, et al. Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine. 2021;73:103646. PMID 34689087 C
18. Kang D, Lim Y, Ahn D, Lee J, Park CJ. Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis. J Med Chem. 2025;68(15):15683-15694. PMID 40739602 D
19. Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R. Cellular senescence in the aging and diseased kidney. J Cell Commun Signal. 2018;12(1):69-82. PMID 29260442 (review)
20. Fimea. Fimea warns: do not use injectable peptides purchased online (29 Jun 2026). Fimea regulator
21. Finland. Lääkeluettelo (Fimea medicines list), 230/2025, annex 1 A: FOXO4-DRI is not named. Finlex regulator
22. European Medicines Agency. Medicine data (data set of 14 Oct 2026): no medicine with FOXO4-DRI. EMA regulator
23. European Medicines Agency. Article 57 product data (EMA/518502/2018 Rev.90, data as of 9 Oct 2026): no product with FOXO4-DRI in any EU/EEA country. EMA regulator
24. World Anti-Doping Agency. The 2026 Prohibited List, class S0 Non-approved substances (in effect from 1 Jan 2026). WADA regulator
25. Fimea. Classification (Luokittelu): basis for classifying a product as a medicine (page updated 3 Apr 2025). Fimea regulator
26. Fuhrmann-Stroissnigg H, Santiago FE, Grassi D, et al. SA-β-galactosidase-based screening assay for the identification of senotherapeutic drugs. J Vis Exp. 2019;(148). doi:10.3791/58133. PMID 31305507 D

Research sources read on 15 Oct 2026 from the publications' abstracts; the original 2017 study also in full text. Regulatory sources checked on 15 Oct 2026.

Evidence levels: A = randomised human trial or meta-analysis · B = observational human study or case series · C = animal study · D = cell or laboratory study · E = not peer-reviewed · regulator = a regulator's assessment or decision, not research evidence. The marker official means official product information (summary of product characteristics or label); it is not research evidence. For a review, the level shows what kind of research the statement rests on. No level: statements that something has not been studied, reviews' interpretations, named hypotheses and the general rules in our certificate-of-analysis guide.

Content is general information about research, not medical advice. If you have symptoms, contact a healthcare professional.