FOX-04 DRI
FOXO4 D-Retro-Inverso senolytic peptide
Mechanism of Action
A D-amino-acid retro-inverso peptide derived from the FOXO4 forkhead domain, linked to a cationic cell-penetrating sequence. Competitively binds the p53 transactivation domain, displacing endogenous FOXO4 and driving p53 nuclear exclusion, which selectively triggers intrinsic apoptosis in senescent cells that otherwise rely on FOXO4–p53 binding for survival.
Key Benefits
- Selectively induces apoptosis in senescent cells while sparing healthy cells (mouse/cell models)
- Restored fitness, fur density, and renal function in fast-aging and naturally aged mice
- Neutralized doxorubicin-induced chemotoxicity in mouse models
- Reduced senescent-fibroblast burden and improved outcomes in keloid scar models
Dosing Protocol
Entirely preclinical. The founding 2017 Cell paper (Baar et al.) used cyclical dosing in mice; no pharmacokinetic or safety data exists in humans. Treat any 'human protocol' from vendors as unverified extrapolation.
Ideal Candidates
Basic longevity/senescence research contexts. No established human use; a caution signal exists from at least one model (see side effects) where senolytic clearance worsened outcomes.
Side Effects & Safety
No human safety data. Important caution: in a pulmonary hypertension mouse model, senescent endothelial cell clearance (via FOXO4-DRI or other senolytics) worsened pulmonary hemodynamics — senolytic effects are not uniformly beneficial across tissue contexts.
Regulatory Status
RestrictedResearch compound only. No 503A listing, no clinical trials in humans — all data is preclinical (mouse/cell models). Not reviewed by FDA for any use.
Evidence & Citations
- Baar MP, et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017;169(1):132-147.
- Bourgeois B, et al. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nat Commun. 2025;16(1):5672.
- Kong YX, et al. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation. Commun Biol. 2025;8(1):299.
- Zhang C, 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.
- Born E, et al. Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression. Circulation. 2023;147(8):650-666.
Frequently asked
What is FOX-04 DRI?+
FOX-04 DRI (FOXO4 D-Retro-Inverso senolytic peptide) is a peptide studied for senolytic and foxo4-p53 disruption. A D-amino-acid retro-inverso peptide derived from the FOXO4 forkhead domain, linked to a cationic cell-penetrating sequence. Competitively binds the p53 transactivation domain, displacing endogenous FOXO4 and driving p53 nuclear exclusion, which selectively triggers intrinsic apoptosis in senescent cells that otherwise rely on FOXO4–p53 binding for survival.
What is the dosing protocol for FOX-04 DRI?+
Literature commonly references No established human dosing (preclinical mouse protocols only) (low) to No established human dosing (preclinical mouse protocols only) (maintenance) via IP (mouse studies), on a not established for human use cycle. Educational reference only — a licensed Stackhaus Health provider sets any personalized protocol.
What is the regulatory status of FOX-04 DRI?+
Research compound only. No 503A listing, no clinical trials in humans — all data is preclinical (mouse/cell models). Not reviewed by FDA for any use.
Where can I access FOX-04 DRI?+
Research-grade FOX-04 DRI is available through Stackhaus Research. For a personalized, provider-reviewed protocol, consult a licensed clinician through Stackhaus Health.