Educational reference, not medical advice. This page summarizes information from published research and regulatory filings for educational purposes. It is not a recommendation to use any compound and should not replace guidance from a licensed healthcare provider. Most peptides discussed here are not approved for the uses described.
What it is
FOXO4-DRI — sold under the trade name Proxofim — is a D-retro-inverso (DRI) peptide based on a fragment of the FOXO4 transcription factor. The "D-retro-inverso" construction means the sequence is reversed and built from D-amino acids rather than the natural L-amino acids; this preserves the side-chain topology while protecting the molecule from proteolytic degradation, dramatically extending in vivo stability.
The peptide is designed to interrupt a specific protein-protein interaction: the binding of FOXO4 to the tumor suppressor p53 in senescent cells. By breaking that interaction, FOXO4-DRI is reported to release p53 to trigger apoptosis selectively in senescent cells while sparing healthy proliferating cells.
History
The compound was introduced by Marjolein Baar and colleagues in the de Keizer lab at University Medical Center Utrecht in a 2017 Cell paper titled "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging." The paper reported that intraperitoneal FOXO4-DRI reduced senescent cell burden in chemotherapy-treated mice, naturally aged mice, and a progeroid mouse model, with downstream restoration of fitness markers including running endurance and renal function.
The paper was widely covered in mainstream science press as an early proof-of-concept for senolytic peptides. Subsequent academic work has used FOXO4-DRI as a tool compound to probe senescent cell biology — in chondrocytes, keloid fibroblasts, testicular Leydig cells, and pulmonary endothelium. A 2025 Nature Communications paper from Bourgeois and colleagues characterized the structural basis of the FOXO4-p53 interaction the peptide disrupts.
Despite the headline 2017 results, FOXO4-DRI has not advanced to human clinical trials. No company has filed an IND specifically for FOXO4-DRI as of 2026. The de Keizer group founded the spinout Cleara Biotech to pursue senolytic drug development; the public clinical programs to date have used different molecules.
Regulatory status
Not approved by any regulator. Not registered in ClinicalTrials.gov or the EU Clinical Trials Register for any indication as of 2026. Not on the FDA 503A bulk substances list; compounding pharmacies in the United States cannot legally prepare it for patients. Sold solely through research chemical channels with explicit not-for-human-use labeling.
Mechanism
FOXO4 is one of four mammalian forkhead box O transcription factors. In senescent cells, FOXO4 binds to and sequesters p53 in nuclear foci, blocking p53's apoptotic activity and allowing the senescent cell to persist. FOXO4-DRI is a fragment of the FOXO4 D-helix that competitively disrupts this interaction. Once freed, p53 activates the intrinsic apoptotic program — but only in cells where FOXO4 is highly expressed and bound to p53, which is the characteristic state of senescent cells. Healthy proliferating cells are reported to be unaffected at the doses studied.
This selectivity is the central claim that distinguishes senolytic peptides from broadly cytotoxic agents. It remains a claim grounded in cell-culture and rodent data; the human selectivity profile has not been established.
Half-life and dosing intervals
D-retro-inverso peptides are far more stable than their L-amino-acid counterparts. Published in vivo half-life estimates for FOXO4-DRI in rodents are on the order of 48 hours, which is exceptionally long for a small peptide. The original Baar et al. dosing schedule was 5 mg/kg by intraperitoneal injection every other day for three doses, repeated in subsequent cycles.
No human dosing data exists. The doses described in observational human use online — typically 0.5 to 1.5 mg per kilogram once every three days for one or two cycles — are direct extrapolations from rodent data with no controlled safety or pharmacokinetic support.
Reconstitution example
FOXO4-DRI is supplied lyophilized in small vials, most commonly 5 mg or 10 mg. A 10 mg vial reconstituted with 2 mL of bacteriostatic water yields 5 mg/mL. On a 1 mL U-100 insulin syringe, 20 units (0.2 mL) delivers 1 mg. Vial's calculator handles the conversion when vial mass and water volume are entered.
What to know
- Preclinical only. All published efficacy data is in cultured cells or rodents. There are no human clinical trials.
- Senolytic by design. The mechanism is selective elimination of senescent cells — a different goal from most peptides in this library, which target healing or regeneration of existing cells.
- Not approved, not compoundable. No regulator has authorized FOXO4-DRI for any use. It cannot be prepared by 503A pharmacies in the United States.
- Dose extrapolation is rough. The leading published rodent dose (5 mg/kg every other day) is far higher than what is typically described in observational human use. Whether the lower human-extrapolated doses produce meaningful senescent cell clearance has not been measured.
- Storage. Lyophilized: refrigerate, protect from light. Reconstituted: refrigerate. The D-retro-inverso construction confers chemical stability, but injectable sterility limits still apply.
Sources
- 1.Baar MP et al. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell.
- 2.Huang L et al. (2021). Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in Bioengineering and Biotechnology.
- 3.Zhang C et al. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency. Aging.
- 4.Bourgeois B et al. (2025). The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nature Communications.