FOXO4-DRI
preclinicalAlso known as: FOXO4-D-Retro-Inverso, Proxofim
**Mechanism of Action** FOXO4-DRI (Proxofim) is a D-retro-inverso peptide designed to mimic the FOXO4 interaction domain, competitively disrupting the binding between FOXO4 and p53 in senescent cells. This interference prevents p53 nuclear sequestration by FOXO4, allowing p53 to translocate to mitochondria and initiate apoptosis. The D-retro-inverso configuration enhances proteolytic stability and bioavailability compared to L-peptides, enabling selective clearance of senescent cells without affecting proliferating or quiescent non-senescent cells. **Key Research Findings** Preclinical studies (17 PubMed references) demonstrate FOXO4-DRI selectively induces apoptosis in senescent human fibroblasts and renal epithelial cells *in vitro*, with efficacy confirmed in mouse models of aging, chemotherapy-induced senescence, and idiopathic pulmonary fibrosis. Treated mice show reduced senescence markers (e.g., p16INK4a, SA-β-gal), improved tissue function (kidney, lung), and extended healthspan without overt toxicity. Notably, FOXO4-DRI does not trigger apoptosis in non-senescent cells, as p53 remains inactive due to intact FOXO4-p53 binding. **Clinical Relevance** As a senolytic agent, FOXO4-DRI holds potential for treating age-related pathologies, chemotherapy side effects, and fibrotic diseases. However, all data remain preclinical; no human trials have been conducted. Limitations include peptide delivery challenges (e.g., renal clearance, tissue penetration) and unknown long-term effects of senescent cell clearance. Further validation in human models is required before clinical translation. For research purposes only — not medical advice.
Key data
C228H388N86O64Research & studies
FOXO4-DRI disrupts FOXO4-P53 interaction, promoting phosphorylated P53 nuclear exclusion and activating BAX and cleaved caspase-3.; FOXO4-DRI selectively induces apoptosis in senescent endothelial cells via the p53/BCL-2/Caspase-3 signaling pathway.; Injection of FOXO4-DRI in naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function.; FOXO4-DRI alleviates endothelial cell senescence induced by oxygen-glucose deprivation, enhancing endothelial cell function.
FOXO4-DRI binds to the disordered p53 TAD2 region, forming a transiently folded complex.; Both the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction.; p53 phosphorylation increases the affinity for both FOXO4 and FOXO4-DRI.; The interaction characterization supports development of p53 inhibitors for senescence-linked diseases like cancer.
Keloids show increased senescent fibroblasts and enhanced senescence-associated secretory phenotype genes.; p53-serine15 phosphorylation is upregulated in keloid fibroblasts.; FOXO4-DRI induces apoptosis and decreases G0/G1 phase cells in keloid models.; FOXO4-DRI promotes nuclear exclusion of p53-pS15, countering apoptosis resistance.
FOXO4-DRI induced apoptosis in senescent Leydig cells.; FOXO4-DRI reduced secretion of senescence-associated secretory phenotype.; FOXO4-DRI improved proliferation of cocultured GC-1 SPG cells.; FOXO4-DRI-treated aged mice showed increased sperm quality and improved spermatogenesis.
FOXO4-DRI induced dissociation of the FOXO4-p53 complex and nuclear exclusion of p53.; FOXO4-DRI treatment in a bleomycin-induced mouse model resulted in milder pathology and less collagen deposition.; FOXO4-DRI reset the distribution of intranuclear p53 and decreased total ECM protein content in fibroblasts.; FOXO4-DRI may be a promising therapeutic approach for pulmonary fibrosis.
Patients with pulmonary arterial hypertension had increased lung senescence markers p16, p21, and DNA damage markers.; Senescent cell elimination via suicide gene or senolytic drugs worsened pulmonary hemodynamics and vessel remodeling in mice.; Loss of pulmonary endothelial cells was observed after senolytic interventions, correlating with disease aggravation.; Monocrotaline-induced pulmonary hypertension in rats was initially slightly reduced but later aggravated by senolytic treatment.
Frequently asked questions
What is FOXO4-DRI?
**Mechanism of Action** FOXO4-DRI (Proxofim) is a D-retro-inverso peptide designed to mimic the FOXO4 interaction domain, competitively disrupting the binding between FOXO4 and p53 in senescent cells. This interference prevents p53 nuclear sequestration by FOXO4, allowing p53 to translocate to mitochondria and initiate
How does FOXO4-DRI work?
D-retro-inverso peptide that disrupts FOXO4-p53 interaction to selectively trigger apoptosis in senescent cells (senolytic).
What is the research status of FOXO4-DRI?
FOXO4-DRI is currently classified as preclinical, with 18 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of FOXO4-DRI?
FOXO4-DRI has a molecular weight of approximately 5358 g/mol (formula C228H388N86O64).
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