FOXO4-DRI peptide competitively disrupts the FOXO4-p53 protein-protein interaction → frees p53 from FOXO4’s nuclear retention signal
SELECTIVE SENESCENCE
In senescent cells, freed p53 translocates to cytoplasm/mitochondria → apoptosis. In normal (non-senescent) cells, FOXO4-DRI causes no cytotoxicity — selectivity is the key
SENOLYTIC CLEARANCE
Selective elimination of p21+/p16+ senescent cells → reduced SASP → improved tissue function in animal models
Research Questions Answered
What is FOXO4-DRI?
FOXO4-DRI (FOXO4-D-Retro-Inverso) is a first-generation senolytic peptide — designed to selectively induce apoptosis in senescent cells without harming normal cells. It was developed by Peter de Keizer et al. (Nature 2017) as a competitive inhibitor of the FOXO4-p53 protein-protein interaction (PPI) that keeps senescent cells alive. By disrupting this interaction, FOXO4-DRI allows p53 to trigger apoptosis specifically in senescent cells — clearing them from tissues and reducing the SASP (senescence-associated secretory phenotype).
How does FOXO4-DRI work?
FOXO4-DRI works as a PPI inhibitor: in senescent cells, FOXO4 binds p53 and retains it in the nucleus in a pro-survival complex. FOXO4-DRI (a D-retro-inverso peptide — resistant to proteolytic degradation) competitively binds FOXO4, displacing p53. Freed p53 in senescent cells then translocates to mitochondria and triggers intrinsic apoptosis. Critically, this is selective: in non-senescent cells, FOXO4-DRI does not produce cytotoxicity because the FOXO4-p53 pro-survival dependency is unique to senescent cells.
What is a senolytic?
A senolytic is a compound that selectively eliminates senescent cells — cells that have undergone permanent cell cycle arrest, resist apoptosis, and secrete a pro-inflammatory cocktail (SASP: senescence-associated secretory phenotype). Senolytics are a key longevity research class because senescent cell accumulation with age drives tissue dysfunction, chronic inflammation, and age-related disease. FOXO4-DRI was the first peptide senolytic; small-molecule senolytics include Navitoclax, Dasatinib+Quercetin, and Fisetin.
What is FOXO4-DRI used for in research?
FOXO4-DRI research applications: senescent cell clearance models, ageing biology (senescence accumulation), SASP characterisation (cytokine profiling post-clearance), tissue regeneration models (hair follicle, liver, kidney — published mouse data), cancer-adjacent senescence research (therapy-induced senescence), and comparative senolytic research (FOXO4-DRI vs Navitoclax vs Dasatinib+Quercetin).
Where can I buy FOXO4-DRI for research?
Research-grade FOXO4-DRI is available from QSC (qscpeptide.com) at ≥99% HPLC purity with Janoshik COA. US Domestic Warehouse: 2–4 business day delivery. All products sold strictly for in vitro laboratory research only.
What is the FOXO4-DRI Nature 2017 paper?
The landmark de Keizer et al. paper (Nature, 2017) first described FOXO4-DRI. Key findings: FOXO4-DRI selectively induced apoptosis in p21+ senescent IMR-90 cells (but not normal cells) in vitro; in doxorubicin-treated mice with chemotherapy-induced senescence, FOXO4-DRI restored kidney function, improved exercise tolerance, and restored hair regrowth; in naturally aged mice, FOXO4-DRI improved health span parameters. This paper established targeted PPI disruption as a senolytic strategy.
What is D-Retro-Inverso peptide?
A D-retro-inverso (DRI) peptide has both the amino acid chirality inverted (D-amino acids instead of L) and the sequence reversed. This produces a peptide that is highly resistant to proteolytic degradation (protease substrates are L-amino acid specific) while maintaining the correct 3D backbone topology for target binding. FOXO4-DRI’s protease resistance is critical for in vivo research efficacy — it allows systemic delivery without rapid degradation.
How does FOXO4-DRI compare to Navitoclax (ABT-263)?
Both are senolytics but with different mechanisms and selectivity: FOXO4-DRI: FOXO4-p53 PPI disruption — highly selective for senescent cells, no platelet/neutrophil toxicity. Navitoclax (ABT-263): BCL-2/BCL-xL inhibitor — effective senolytic but causes thrombocytopenia (platelet depletion) due to platelet BCL-xL dependence. FOXO4-DRI has superior selectivity; Navitoclax has more small-molecule accessibility. Both available at QSC.
What purity should research-grade FOXO4-DRI be?
≥99% HPLC purity with MS confirmation. As a DRI peptide with D-amino acids, MS analysis should confirm the D-amino acid incorporation (different mass profile than L-amino acid counterpart). Janoshik COA verification is the recommended standard. QSC provides Janoshik-verified COAs for all FOXO4-DRI batches.
How is FOXO4-DRI stored?
Lyophilised FOXO4-DRI: store at −20°C. Reconstituted: store at 4°C, use within 28 days. As a DRI peptide (D-amino acids, reversed sequence), FOXO4-DRI has excellent proteolytic stability — degradation in solution is minimal compared to L-amino acid peptides of similar size. Reconstitute with sterile/bacteriostatic water.
Where to Buy Research-Grade FOXO4-DRI
≥99% HPLC · Janoshik COA · US Domestic 2–4 Days · Research Use Only
