FOXO4-DRI Research

FOXO4-DRI research began with a single 2017 paper in Cell, and it has stayed entirely preclinical ever since.^[1] The compound is a synthetic peptide designed to disrupt the interaction between FOXO4, a transcription factor, and the tumor suppressor p53.^[1] Published work on it has used purified proteins, cultured cells, donor tissue, mice, or rats.^{[1][2][6][11]} No human being has been given FOXO4-DRI in any published study, and no trial of it has ever been registered on ClinicalTrials.gov.^[17][19] One animal study has reported harm rather than benefit.^[12]

What FOXO4-DRI is

FOXO4-DRI is a 46-residue peptide built entirely from D-amino acids in a retro-inverso arrangement, which is what the DRI in its name denotes.^[1] PubChem records it under CID 168431240 and CAS 2460055-10-9, with molecular formula C228H388N86O64 and molecular weight 5358.^[16] That figure matches the weight printed in the founding paper's methods.^[1]

The peptide joins two distinct parts: an N-terminal stretch derived from a region of FOXO4 that diverges from FOXO1 and FOXO3, and a C-terminal polycationic cell-penetrating sequence.^[1] That second part was intended as a delivery vehicle, and later structural work found it does more than deliver.^[2]

The name Proxofim returns no records in PubMed and none in PubChem, and it is not an international nonproprietary name.^[16][19] It is a supplier alias. A name-based PubChem lookup is also unreliable here, because an unrelated cosmetic hexapeptide near 949 in molecular weight wrongly carries a FOXO4-DRI synonym.^[16] Research-grade FOXO4-DRI corresponds to the peptide described here.

How FOXO4-DRI is thought to work

In senescent cells, p53 phosphorylated at serine 15 is held in the nucleus in association with FOXO4. The founding paper proposed that FOXO4-DRI competes with endogenous FOXO4 for that binding. In cultured human IMR90 fibroblasts it caused nuclear exclusion of phosphorylated p53 and caspase-3/7-dependent apoptosis, in senescent cells but not in controls.^[1]

Solution NMR work published in 2025 found that FOXO4-DRI binds the disordered transactivation domain of p53 in a complex that is only transiently folded.^[2] This is structural work in vitro rather than a cellular or animal result.

That study also complicates the specificity story, because both the FOXO4-derived region and the cationic cell-penetrating tail contributed to binding.^[2] A polycationic sequence contributing to target engagement leaves open how much of the observed activity is sequence-specific FOXO4 mimicry.^[2]

Preclinical FOXO4-DRI research

The founding paper reported three mouse experiments.^[1] In a doxorubicin chemotoxicity model it reduced senescence markers and lowered plasma AST.^[1] In fast-aging and naturally aged mice it reported improved fitness, fur density, and plasma urea and creatinine.^[1]

That paper's naturally aged fur endpoint used male mice only, and most of those males already showed hair loss at baseline.^[1] The paper's tolerability statement is heavily conditioned. Its authors wrote that more thorough analysis is required, and that the compound appeared well tolerated only as far as tested there.^[1]

Selectivity in human cells

An independent group at the University of Pittsburgh tested selectivity in primary human chondrocytes. In vitro, FOXO4-DRI removed more than half of a senescence-enriched human chondrocyte population while not significantly affecting younger controls.^[3]

A separate study used patient-derived keloid tissue and fibroblasts held in culture. FOXO4-DRI promoted apoptosis and nuclear exclusion of serine-15-phosphorylated p53 in that human material.^[6] No patient was dosed.

Rodent research

A group at Sun Yat-sen University published two aged-mouse studies of the testis, reporting partial relief of age-related testosterone insufficiency and improved spermatogenesis.^[4][5] Those two papers share senior authors and each first author appears on both, so they are one laboratory rather than two.

Other mouse work reports radiosensitization of non-small cell lung cancer, two separate bleomycin pulmonary fibrosis studies, and effects on endothelial senescence in aged and progeroid animals.^{[7][8][9][10]} An NIH-funded group in the United States dosed rat pups in a hyperoxic bronchopulmonary dysplasia model, reporting reduced senescence and improved alveolar complexity.^[11]

Negative and null findings

Born and colleagues reported in Circulation that senolytic clearance of senescent pulmonary endothelial cells can worsen pulmonary hypertension.^[12] FOXO4-DRI was one of the two senolytics tested, and in the relevant mouse model it produced hemodynamic deterioration and loss of pulmonary endothelial cells against controls.^[12] Those cells made up roughly 30 percent of senescent lung cells in mice under normoxia.^[12] The authors concluded that eliminating them by senolytic intervention may worsen pulmonary hemodynamics, and the paper drew an accompanying editorial in the same issue.^[12][13]

A published failed replication also exists, from an independent group testing FOXO4-DRI in human endometrial mesenchymal stromal cells made senescent by oxidative stress. Neither FOXO4-DRI nor the comparator senolytics tested killed those cells selectively, which the authors reported as an absence of senolysis.^[14] That in vitro result covers a human cell type the other selectivity studies did not reach.

The Pittsburgh chondrocyte study carries its own null: in vitro, FOXO4-DRI pretreatment did not enhance the chondrogenic potential of those human cells.^[3]

The founding paper contains a null as well, because where senescent cells in mice were already being cleared genetically, FOXO4-DRI did not further enhance the effect.^[1]

The founding paper's headline aged-mouse phenotype has not been independently replicated as a combination. Later aged-rodent studies report different endpoints in different tissues.^{[4][5][10][11]} No study identified in the published record has re-tested that paper's specific pairing of fitness, fur density, and renal markers in naturally aged mice.^[19]

Human research

No human has been dosed with FOXO4-DRI in any published study, and no trial of it has ever been registered on ClinicalTrials.gov.^[17][19] Nine years after the founding paper, no human pharmacokinetic, safety, or tolerability data has been published.^[19] Human material appears in this literature only as cultured cells and donor tissue.^[3][6][14]

FOXO4-DRI is not approved for human therapeutic use, and no marketing approval has been identified in any jurisdiction.^[18] That search reached US federal drug records directly, while registers in other jurisdictions were not directly searchable.^[18] It is not registered as a substance with the US FDA, and PubChem returns no unique ingredient identifier.^[16][18] This is not a withdrawn or refused application, because none appears to have been filed.^[18]

Limitations and current research directions

Every published in vivo experiment administered the peptide by injection, and no oral, subcutaneous, or intranasal study has been published.^[1][4][11] There is also no published pharmacokinetic or repeat-dose toxicology data.^[19]

The founding paper's disclosures sit in its acknowledgements, where one author is identified as a co-founder and shareholder of a senolytics company.^[1] The same acknowledgement states that the companies named there were not involved in that research.^[1] That paper also states that the compound is subject to patent applications.^[1] The 2025 structural study is more concentrated still. It was partly funded by the company set up to commercialize this work, and two of its authors hold shares in that company.^[2] They also state that the reported binding studies relate to their patents.^[2]

The strongest mechanistic evidence was therefore produced by parties who own the chemistry, while the decisive negative result came from an independent consortium with no stake.^[2][12] Independent groups with no stake have reported both positive and negative findings.^{[3][6][11][12][14]}

The inventors stated in 2025 that optimizing FOXO4-DRI produced a distinct class of compounds, two of which are in preclinical development in oncology.^[2] A separate group's 2025 peptide was likewise designed to improve on FOXO4-DRI.^[15] Both treat it as a starting hit rather than a finished therapeutic.

Conclusion

FOXO4-DRI is an early preclinical research tool with a nine-year record of purified protein, cell, mouse, and rat studies. Several came from independent groups reporting selective effects on senescent cells in vitro. Against that, one independent animal study reported harm and one independent in vitro study reported no senolysis at all.^[12][14] No treated human subject appears anywhere in this literature.^[19]

FOXO4-DRI is a research compound, supplied for laboratory research use only.

Frequently Asked Questions

Has FOXO4-DRI been tested in humans? No human has been dosed with FOXO4-DRI in any published study, and no trial of it has ever been registered on ClinicalTrials.gov.^[17][19] No human pharmacokinetic, safety, or tolerability data has been published, and human material appears here only as cultured cells and donor tissue.^{[3][6][14][19]}

Is Proxofim a different compound from FOXO4-DRI? Proxofim is a supplier alias for the same peptide, not a separate compound and not an international nonproprietary name.^[16][19] A name-based PubChem lookup is unreliable here, because an unrelated cosmetic hexapeptide near 949 in molecular weight wrongly carries a FOXO4-DRI synonym.^[16] The correct values are C228H388N86O64 at molecular weight 5358.^[16]

Has any study reported harm from FOXO4-DRI? Yes, in mice. Born and colleagues reported that FOXO4-DRI produced hemodynamic deterioration and loss of pulmonary endothelial cells in a mouse model of pulmonary hypertension.^[12] The authors concluded that eliminating those senescent cells by senolytic intervention may worsen pulmonary hemodynamics.^[12]

References

1. 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. doi:10.1016/j.cell.2017.02.031. PMID 28340339.
2. 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. Nat Commun. 2025;16(1):5672. doi:10.1038/s41467-025-60844-9. PMID 40593617.
3. 3

   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.
4. 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 (Albany NY). 2020;12(2):1272-1284. doi:10.18632/aging.102682. PMID 31959736.
5. 5

   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. doi:10.1016/j.exger.2024.112522. PMID 39025385.
6. 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. Commun Biol. 2025;8(1):299. doi:10.1038/s42003-025-07738-0. PMID 39994346.
7. 7

   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. doi:10.1172/jci.insight.146334. PMID 34877934.
8. 8

   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. doi:10.1111/jcmm.17333. PMID 35510614.
9. 9

   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. doi:10.1007/s00210-023-02452-2. PMID 37074394.
10. 10

    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. doi:10.3389/fbioe.2025.1729166. PMID 41625068.
11. 11

    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. doi:10.1165/rcmb.2023-0038OC. PMID 37874230.
12. 12

    Born E, Lipskaia L, Breau M, et al. Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation. 2023;147(8):650-666. doi:10.1161/CIRCULATIONAHA.122.058794. PMID 36515093.
13. 13

    Rabinovitch M. Are senolytic agents guilty of overkill or inappropriate age discrimination? Circulation. 2023;147(8):667-668. doi:10.1161/CIRCULATIONAHA.122.060247. PMID 36802881.
14. 14

    Deryabin PI, Shatrova AN, Borodkina AV. Targeting multiple homeostasis-maintaining systems by ionophore nigericin is a novel approach for senolysis. Int J Mol Sci. 2022;23(22):14251. doi:10.3390/ijms232214251. PMID 36430735.
15. 15

    Kang D, Lim Y, Ahn D, et al. Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis. J Med Chem. 2025;68(15):15683-15694. doi:10.1021/acs.jmedchem.5c00537. PMID 40739602.
16. 16

    PubChem Compound Summary, CID 168431240 (FOXO4-DRI). National Library of Medicine. PUG-REST property, xrefs/RN and xrefs/RegistryID queries, retrieved 2026-08-28. https://pubchem.ncbi.nlm.nih.gov/compound/168431240
17. 17

    ClinicalTrials.gov, National Library of Medicine. API v2, `query.term=FOXO4-DRI` returns totalCount 0 and `query.term=proxofim` returns totalCount 0. Retrieved 2026-08-28. https://clinicaltrials.gov
18. 18

    openFDA, US Food and Drug Administration. Drug label and Drugs@FDA endpoints, field-qualified queries on `openfda.substance_name` and `openfda.generic_name` for FOXO4-DRI, FOXO4 and proxofim, all NOT_FOUND. Retrieved 2026-08-28. https://open.fda.gov
19. 19

    PubMed, National Library of Medicine. E-utilities searches: `proxofim` returns 0 records; the phrase search `"FOXO4-DRI"` returns 19 records, none of them a clinical trial by publication type. Retrieved 2026-08-28. https://pubmed.ncbi.nlm.nih.gov