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FOXO4-DRI

Also known as FOXO4 D-Retro-Inverso peptide, FOXO4-p53 interfering peptide, Proxofim

Experimental senolytic peptide from a 2017 mouse study, sold to consumers despite zero human safety data.

preclinical Immune & longevity research chemical

At a glance

Category
Immune & longevity
Status
research chemical
Route
intraperitoneal and intravenous in the mouse studies; injected subcutaneously in unvalidated consumer use
Half-life
No published pharmacokinetics in any species. D-amino acid retro-inverso peptides are, by design, resistant to proteolysis and generally circulate far longer than their L-counterparts - which in this case is a safety concern rather than a convenience, because there is no mechanism to clear it quickly if something goes wrong.
Molecular weight
approximately 4.8 kDa
Sequence
A 34-residue retro-inverso peptide built entirely from D-amino acids, derived from the FOXO4 forkhead domain sequence that contacts p53, fused to a cell-penetrating stretch. The retro-inverso design reverses the residue order and mirrors every stereocentre, so the side-chain topology is approximately preserved while proteases no longer recognise the backbone. Published sequence renderings differ in the last few residues between sources and are not reproduced here.

FOXO4-DRI does not appear as an intervention in any registered clinical study: a search of the ClinicalTrials.gov registry in July 2026 returns zero studies for the term 4. It is not approved by any regulator, has no investigational new drug status that has been made public, and PeptideX has found no published protocol under which it has been given to a human being. It is nevertheless sold online to consumers as an anti-ageing injectable. This is the widest gap between evidence and commercial availability of any compound in this reference: the entire human safety database is empty.

Doping status: Not listed by name; as a non-approved substance it falls under S0 and is therefore prohibited at all times

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

This is a short entry. There is little or no published research on this compound, so there is correspondingly little to report. Empty dosing or reconstitution sections mean no credible figures exist — not that they were left out.

Mechanism of action

In senescent cells, the transcription factor FOXO4 sequesters p53 in nuclear foci. p53 that is bound to FOXO4 cannot relocate to the mitochondria and cannot trigger apoptosis, which is part of why senescent cells persist rather than dying. FOXO4-DRI is a decoy: it binds p53 competitively at the FOXO4 interface, displaces endogenous FOXO4, and releases p53 to move to the mitochondria and initiate apoptosis. Because senescent cells are the ones that depend on this interaction for survival, the effect is expected to be selective for them - that selectivity is the whole premise of the compound.

The corollary is a real hazard: the drug works by deliberately unleashing p53-driven apoptosis. If the selectivity is imperfect at a given dose, in a given tissue, or in a person with an altered p53 pathway, the mechanism does not fail gracefully. Cell-penetrating peptides of this class are known to distribute broadly, and there is no published tissue distribution study for this molecule in any species.

What the research shows

One well-executed 2017 mouse paper, a handful of follow-up rodent and cell-culture studies, and nothing else. There is no human data of any kind - not efficacy, not safety, not pharmacokinetics, not a single dose ever administered to a person under a published protocol. Anyone injecting this is not taking a drug with thin evidence; they are taking a drug with no human evidence at all.

Research in humans

No published human studies. None. No phase I trial, no case series, no registry, no tolerability data, no pharmacokinetic study, no maximum tolerated dose. Nothing has been published about what FOXO4-DRI does in a human body.

Animal and lab research

Baar and colleagues (Cell, 2017) reported that FOXO4-DRI selectively induced apoptosis in senescent but not proliferating or quiescent cells in culture, and that in mice it counteracted doxorubicin-induced toxicity, and in fast-ageing Xpd-TTD mutant mice and in naturally aged mice restored fur density, renal function and running-wheel activity 1. It is a careful paper with a coherent mechanism, and it deserves the attention it received. Follow-up work has been sparse: Huang and colleagues (2021) showed selective removal of senescent cells from expanded human chondrocytes in vitro 2, and a 2020 study in Aging reported improved testosterone secretion via clearance of senescent Leydig cells in aged mice 3. All of it is cell culture and rodent.

Caveats. The rodent efficacy readouts - fur density, wheel running, renal markers - are not endpoints that translate reliably to human outcomes. Doses were intraperitoneal in mice, a route with different exposure from human subcutaneous injection, and no allometric scaling has been validated. There is no chronic toxicology study, no carcinogenicity study, no reproductive toxicity study and no immunogenicity assessment, which matters because a D-amino acid peptide is a foreign structure the body cannot break down normally. Nearly a decade after the original paper, no company has taken FOXO4-DRI into a clinical trial - and in a field with abundant funding for senolytics, that absence is informative. Grey-market product is additionally of unverified identity and purity; a 34-mer of all-D amino acids is a demanding synthesis and correct assembly cannot be assumed.

What it is used for

  • Preclinical research tool for testing the senolytic hypothesis 1
  • Sold online and self-administered as an anti-ageing injectable, with no validated indication, no validated dose and no human safety data

Dosing

  • There is no human dose. Not a poorly established one - none at all. No maximum tolerated dose, no pharmacokinetics, no dose-response curve, and no clinical protocol to take a starting dose from: ClinicalTrials.gov lists no study of this compound 4.
  • The mouse study used intraperitoneal dosing in a three-days-on schedule 1; converting a mouse intraperitoneal dose to a human subcutaneous dose without pharmacokinetic data is guesswork, and any online protocol presenting a figure in milligrams is inventing it.
  • Deliberately triggering p53-mediated apoptosis at an unknown dose, in unknown tissues, with a protease-resistant molecule that cannot be cleared quickly, is not a risk that can be estimated from the available data.
  • What little circulates does not amount to a protocol, and no protocol section is given below on purpose. FOXO4-DRI is sold as lyophilised powder in small vials and injected subcutaneously by a handful of self-experimenters; the milligram figures that surface in forum posts do not converge, are copied from vendor pages and dosage-aggregator tables rather than derived from any pharmacology, and a large part of the discussion is other users warning against using it at all. Some quote a fraction of a vial once every week or two, others a few milligrams; the numbers share nothing but their absence of a basis. Assembling these into a tidy schedule would manufacture a coherence the practice does not have, and this entry already carries the widest gap between evidence and availability on the site.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Reconstitution

No reconstitution guidance is given here, because giving it would imply that a defensible human dose exists. It does not.

Safety

Side effects

  • Unknown in humans - no person has been monitored on this compound in any published study
  • In the mouse work, effects on bone marrow were noted with senolytic dosing 1; p53-driven apoptosis in proliferating compartments such as marrow, gut epithelium and hair follicle is the predictable class risk
  • Immunogenicity against a wholly D-amino acid foreign peptide has not been assessed
  • The absence of reported side effects in the literature reflects the absence of humans in the literature, not safety

Do not use if

  • Everyone, in the practical sense: there is no indication for which the risk-benefit ratio has been established in a human being
  • Any current, past or suspected malignancy - the compound acts directly on the p53 apoptotic axis and its behaviour in a tumour with altered p53 is unstudied
  • Concurrent or recent chemotherapy - the interaction with cytotoxic agents was examined only in the context of doxorubicin toxicity in mice 1 and is unpredictable in people
  • Pregnancy, breastfeeding, children and adolescents - no data, and a mechanism that kills cells by releasing p53 is a poor candidate for use during development
  • Any haematological disorder or marrow suppression

Interactions

Not studied in humans. In mice, FOXO4-DRI was given in the context of doxorubicin toxicity, so an interaction with cytotoxic chemotherapy is the one relationship that has been examined at all - in rodents 1. Additive effects with other senolytics (dasatinib plus quercetin, fisetin, navitoclax) are conceivable and entirely untested.

Sources