FOXO4-DRI

Summary

FOXO4-DRI is a synthetic cell penetrating peptide built from D-amino acids in reverse order so it resists breakdown; it pries the transcription factor FOXO4 off p53 inside senescent cells, which releases p53 to trigger their death. In a 2017 Cell paper it selectively killed senescent cells and restored running capacity, fur density, and kidney function in fast aging and naturally old mice, and later mouse studies reported improved testosterone and sperm production in old males. There is no human trial, no FDA review, and no lawful source; it is prohibited by WADA under section S0.

What is FOXO4-DRI?

FOXO4-DRI is a synthetic D-amino acid retro-inverso peptide (about 46 residues) that disrupts the FOXO4 to p53 interaction in senescent cells. It is also known as FOXO4 D-retro-inverso peptide, FOXO4-DRI senolytic, Proxofim, FOXO4 DRI.

How does it work?

In senescent cells, FOXO4 binds p53 in the nucleus and keeps it from triggering apoptosis, which lets damaged cells persist and secrete inflammatory factors (the senescence associated secretory phenotype). FOXO4-DRI is a D-retro-inverso version of the FOXO4 fragment that binds p53; it competes with native FOXO4, freeing p53 to move to mitochondria and start cell death selectively in senescent cells. The D-amino acid backbone resists proteases, which gives it a longer half life than a normal peptide. All of this is shown in cell culture and mice.

What does the evidence say about FOXO4-DRI?

One high profile mouse study and a few follow ups. Baar et al. 2017 showed FOXO4-DRI (5 mg/kg intraperitoneally, 3 doses over a week or repeated cycles) selectively killed senescent cells in culture and in mice, neutralized chemotherapy induced toxicity, and in fast aging XpdTTD/TTD and naturally aged mice restored fur density, running wheel activity, and kidney function markers. Zhang et al. 2020 reported that FOXO4-DRI cleared senescent Leydig cells and raised testosterone in aged mice, and Li et al. 2024 reported improved spermatogenesis in aged mice. No human study of any kind has been published.

Human evidence

No indexed human study identified. No pharmacokinetic, safety, or efficacy data in humans exist.

Animal evidence

Baar 2017: in aged and progeroid mice, FOXO4-DRI reduced senescent cell burden and improved fur density, physical activity, and renal function within weeks; in doxorubicin treated mice it reduced chemotherapy toxicity. Zhang 2020: intraperitoneal FOXO4-DRI in aged male mice removed senescent Leydig cells and raised serum testosterone. Li 2024: in aged mice, FOXO4-DRI reduced senescence associated secretory phenotype output from Leydig cells and improved spermatogenesis.

Key studies

Conditions studied

Is FOXO4-DRI legal in the United States?

FDA and compounding status

FOXO4-DRI is not an FDA approved drug and PeptideAgent has not identified it on the FDA 503A bulks nomination lists or in any Pharmacy Compounding Advisory Committee review. Without a listing, a 503A pharmacy cannot lawfully compound it as a bulk substance. It is not eligible for 503B outsourcing. Products sold under this name are not lawful for human use and, because the peptide is long and made entirely of D-amino acids, are expensive and difficult to verify.

WADA status

WADA prohibited. Athletes subject to anti-doping testing should treat this as prohibited at all times unless the current prohibited list says otherwise.

Regulatory timeline

No regulatory events recorded.

Full tracker for FOXO4-DRI or the category-wide tracker.

What published studies of FOXO4-DRI used

Ranges below are reported from published studies and labeling only. PeptideAgent does not recommend doses or protocols.

Not established in human literature. Mouse studies used 5 mg/kg intraperitoneally, given as 3 doses on alternating days, sometimes repeated in cycles. No human dose, route, or pharmacokinetic study has been published.

Routes reported

What are the side effects and interactions of FOXO4-DRI?

Side effects

Interactions

Contraindications

How do people access FOXO4-DRI legally?

Typical cost: Not available through licensed channels. Products sold as research chemicals are not lawful for human use and are not verified for identity or purity.

• Rules by state
• Verified provider directory

What's actually offered, and what that means for you

Licensed compounding pharmacies, clinics, and telehealth prescribers openly offer many unapproved peptides, and prescribers write prescriptions for them. That does not make FOXO4-DRI lawful. FOXO4-DRI is not FDA approved and not on the 503A bulks list, so a pharmacy has no lawful basis to compound it. [4] [7]

Enforcement is uneven. FDA mostly acts through warning letters to compounders and online sellers, Category 2 safety listings, and import alerts that let it detain shipments, rather than stopping every pharmacy. State pharmacy boards oversee pharmacies day to day, and their rules differ. [7] [8] [9] [10] [11]

What changes for you

• No FDA review of the product: FDA does not check a compounded drug's safety, effectiveness, or quality before it is sold. [11]
• Identity, purity, sterility, and dose accuracy can vary from batch to batch. [7]
• Insurance rarely covers it, so you usually pay cash.
• For tested athletes, FOXO4-DRI is prohibited at all times on the WADA list, whatever the source. [6]

What to check

These checks lower some risks, but they do not make an unlawfully compounded product lawful or safe. Check for:

• A 503A pharmacy licensed in your state (your state board of pharmacy publishes license lookups). [11]
• A real evaluation by a licensed prescriber, not just an online form.
• A certificate of analysis for the specific batch.

Frequently asked questions

Decisions about starting, stopping, or combining any treatment belong with a licensed clinician who knows your history.

Sources

Numbered citations above point to these primary sources. PubMed entries link to the indexed abstract.