What is FoxO4‑DRI?

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What is FOXO4-DRI?

FOXO4-DRI (FOXO4-D-Retro-Inverso) is an experimental senolytic peptide designed to selectively induce apoptosis in senescent cells by disrupting the interaction between FOXO4 and p53, thereby promoting p53 nuclear exclusion and triggering cell death specifically in senescent cells while sparing healthy cells. 1

Mechanism of Action

  • FOXO4-DRI works by perturbing the FOXO4-p53 protein interaction, which is critical for maintaining senescent cell viability 1
  • The peptide causes selective p53 nuclear exclusion in senescent cells, triggering cell-intrinsic apoptosis 1
  • The disordered FOXO4-DRI binds to the disordered p53 transactivation domain (p53TAD2) and forms a transiently folded complex, with both the FOXO4-derived region and the cationic cell permeability peptide contributing to the interaction 2
  • P53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI, making senescent cells (which have elevated p53-serine15 phosphorylation) particularly vulnerable 2, 3

Preclinical Evidence

  • In senescent cells, FOXO4-DRI neutralized doxorubicin-induced chemotoxicity and was well tolerated in vivo 1
  • The peptide restored fitness, fur density, and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice 1
  • FOXO4-DRI improved testicular microenvironment and alleviated age-related testosterone secretion insufficiency in naturally aged mice by targeting senescent Leydig cells 4
  • In bleomycin-induced pulmonary fibrosis models, FOXO4-DRI decreased senescent cells, downregulated senescence-associated secretory phenotype (SASP) expression, and attenuated morphological changes and collagen deposition 5
  • The peptide shows preferential killing of TGF-β-induced myofibroblasts compared to normal fibroblasts, leading to downregulation of extracellular matrix receptor interaction pathways 5
  • In keloid models, FOXO4-DRI promoted apoptosis and decreased G0/G1 phase cells while inducing p53-pS15 nuclear exclusion 3

Clinical Context and Limitations

  • FOXO4-DRI remains an experimental compound with no current clinical approval or guideline recommendations for human use
  • All evidence comes from preclinical animal models and in vitro studies 1, 4, 5, 3
  • The compound represents a proof-of-concept that therapeutic targeting of senescent cells is feasible and can restore tissue homeostasis after damage has occurred 1
  • FOXO4 is identified as a pivot in senescent cell viability, making it a rational therapeutic target for age-related conditions 1

Potential Applications Under Investigation

  • Age-related tissue dysfunction and restoration of homeostasis in naturally aged organisms 1
  • Chemotherapy-induced toxicity mitigation 1
  • Male late-onset hypogonadism through targeting senescent Leydig cells 4
  • Pulmonary fibrosis by clearing senescent myofibroblasts 5
  • Keloid treatment by inducing apoptosis in senescent fibroblasts 3

References

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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