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Peptide Encyclopedia / FOXO4-DRI

Encyclopedia

FOXO4-DRI

FOXO4-DRI is a senolytic peptide designed to break the FOXO4-p53 interaction in senescent cells and trigger their targeted death. Evidence stops at mouse and lab studies with no human trials, and it trades as a gray-market research chemical, not an FDA-approved drug. Educational only, not medical advice.

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CategoryLongevity / Anti-aging
Regulatory statusNot FDA-approved; research chemical / gray-market in the US.

Mechanism

A senolytic peptide designed to disrupt the FOXO4-p53 interaction in senescent cells. By displacing p53 from FOXO4, it promotes nuclear exclusion of FOXO4 and p53-driven apoptosis selectively in senescent cells. The D-retro-inverso design (mirror-image D-amino acids in reversed sequence) is intended to resist proteolysis. First described by de Keizer and colleagues (Cell, 2017).

Half-life

uncertain / limited human pharmacokinetic data; the DRI design is intended to increase metabolic stability, but no validated human PK exists.

Regulatory status

Not FDA-approved; research chemical / gray-market in the US. Not an approved drug anywhere; remains an experimental senolytic candidate. Not on FDA compounding lists.

Safety

No human safety data. Senolytic apoptosis induction carries theoretical risks (e.g., effects on healthy cells, tissue/immune effects); only mouse data exist. Gray-market product purity and correct D-amino-acid synthesis are unverified and hard to confirm. High caution warranted.

Evidence

Preclinical. Notable, peer-reviewed mouse and in-vitro studies (originating largely from the de Keizer lab and a limited set of follow-ups), but no completed human clinical trials demonstrating safety or efficacy.

Sources

  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. https://pmc.ncbi.nlm.nih.gov/articles/PMC5556182/
  2. 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. https://pmc.ncbi.nlm.nih.gov/articles/PMC7053614/
  3. Le HQ, Lie KK, Giroud-Gerbetant J, et al. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in Bioengineering and Biotechnology. 2021;9:677576. https://pubmed.ncbi.nlm.nih.gov/33996787/
  4. Bourgeois B, Spreitzer E, et al. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nature Communications. 2025;16:5672. https://pubmed.ncbi.nlm.nih.gov/40593617/
  5. Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nature Metabolism. 2020;2(11):1265-1283. https://pubmed.ncbi.nlm.nih.gov/33199924/

PepWise is an informational and educational tracking tool, not medical advice and not a medical device. FOXO4-DRI may be experimental, restricted, or prescription-only; many research peptides are not FDA-approved. Consult a licensed healthcare provider before starting, changing, or stopping any protocol. Operated by STC Consulting, Inc.