FOXO4-DRI
D-retro-inverso cell-penetrating peptide that blocks the FOXO4 and p53 interaction (senolytic)
Status
Not approved
A laboratory research compound with no approval anywhere, no registered clinical trial and no pharmacopoeial monograph. It was not among the peptide bulk substances FDA considered for US pharmacy compounding in 2026, so there is no regulatory pathway for human use and material sold online is research-grade only.
Evidence
Animal data only
Everything known about it comes from cell culture and mouse experiments; no human has been dosed in a published study.
In sport
WADAProhibited (WADA)
A 46-residue mirror-image peptide designed to kill senescent cells by breaking the link between the proteins FOXO4 and p53. It has only been tested in cells and mice and is sold as a research chemical.
Structure
46 residuesPoint at a bead, or focus the chain and use the arrow keys, to name it. Pick a chemistry to highlight it.
D-form (mirror image), shown in lower case
Sequence as text
FOXO4-DRI: H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-G-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-G-G-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-G-OH
What it is used for
- Clearing senescent cells to reverse features of ageing (claimed, unproven)
- Restoring fur density, kidney function and fitness in aged and progeroid mice (studied)
- Removing senescent cells from cultured human chondrocytes, keloid fibroblasts and endothelial cells (studied)
How it works
Cells that have stopped dividing after damage, called senescent cells, accumulate with age and release inflammatory signals. Many survive because the protein FOXO4 holds p53 in the nucleus and keeps it from triggering cell death. FOXO4-DRI competes for the same binding site on p53, pushing p53 out of the nucleus and letting the senescent cell die, while cells that are not senescent are largely unaffected. NMR work in 2025 mapped that competition to the disordered second transactivation domain of p53.
How strong the evidence is
Animal data only
Baar and colleagues reported in Cell in 2017 that FOXO4-DRI selectively killed senescent cells and that dosing in fast-ageing and naturally aged mice restored fur density, kidney function and running capacity. Later mouse work reported effects on Leydig cell senescence and testosterone, and on spermatogenesis in aged mice. Cell studies show selective removal of senescent human chondrocytes and keloid fibroblasts. A 2025 Nature Communications study characterised the binding to the p53 transactivation domain. There is no human trial, no pharmacokinetic data in people and no safety study in humans.
Risks and side effects
- No human data: safety, dosing and even basic tolerability in people are unknown
- It works by pushing cells into p53-driven cell death, and the consequences of doing that broadly in a living person, including effects on stem cells and wound healing, have not been established
- Senescent-cell clearance is not universally beneficial: in one model, removing senescent cells promoted pulmonary hypertension
- A 46-residue synthetic peptide carries a real risk of immune reactions, and research-grade material has unverified purity, endotoxin load and sterility
- Prohibited in sport at all times under WADA class S0, which covers substances with no approval by any government health regulator
Regulatory status
Status by country
| Jurisdiction | Status | Source |
|---|---|---|
| USUnited States | No authorised medicine | Source 7 |
| EUEuropean Union | No authorised medicine | Source 8 |
| UKUnited Kingdom | No authorised medicine | Source 9 |
| AUAustralia | No authorised medicine | Source 10 |
| CACanada | No authorised medicine | Source 11 |
Sources
- 01Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging(opens the source in a new tab)
- 02The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI(opens the source in a new tab)
- 03FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice(opens the source in a new tab)
- 04Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression(opens the source in a new tab)
- 05FOXO4-DRI, CID 168431240(opens the source in a new tab)
- 06The 2026 Prohibited List, International Standard(opens the source in a new tab)
- 07Drugs@FDA: FDA-Approved Drugs(opens the source in a new tab)
- 08Find medicine: centrally authorised medicines(opens the source in a new tab)
- 09MHRA Products: active substances beginning with F(opens the source in a new tab)
- 10Australian Register of Therapeutic Goods (ARTG)(opens the source in a new tab)
- 11Drug Product Database online query(opens the source in a new tab)
Educational information, not medical advice. Talk to a licensed clinician before starting, stopping or changing any medicine.