Key papers ✓ 5✗ 1~ 1

• ✓ Positive animalCell · 2017

  Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

  Humans + animals

  Preclinical study designing a FOXO4 peptide that disrupts FOXO4-p53 interaction

  Original Cell study: FOXO4-DRI selectively triggered apoptosis in senescent cells, counteracted doxorubicin chemotoxicity, and restored fitness, fur density and kidney function in fast-aging and naturally aged mice.

  Study details

  Studied

  Senescent human cells in vitro; doxorubicin-treated, fast-aging XpdTTD/TTD and naturally aged mice

  Main outcome

  Apoptosis of senescent cells; chemotoxicity, fitness, fur density, renal function

  Authors' conclusion

  The FOXO4 peptide selectively induced apoptosis in senescent cells, neutralized doxorubicin chemotoxicity and restored fitness, fur density and renal function in aged mice, as shown by the authors.

  Limitations

  Mouse and cell study only; numbers not in the abstract.

  DOI 10.1016/j.cell.2017.02.031PubMed 28340339Free full text
• ✗ Negative animalCirculation · 2023

  Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.

  Humans + animals

  Human tissue analysis plus animal models with senescent-cell clearance (suicide gene, ABT263, FOXO4-DRI)

  In mouse and rat pulmonary hypertension models, clearing senescent cells (including with FOXO4-DRI in serotonin-transporter mice) worsened pulmonary hemodynamics and caused loss of pulmonary endothelial cells.

  Study details

  Studied

  Patients with pulmonary arterial hypertension (lung tissue) and mouse and rat pulmonary hypertension models

  Compared with

  Relevant control animals

  Main outcome

  Pulmonary hemodynamics, vessel remodeling, pulmonary endothelial cell loss

  Authors' conclusion

  Eliminating senescent pulmonary endothelial cells with senolytic interventions, including FOXO4-DRI in SM22-5-HTT+ mice, may worsen pulmonary hemodynamics.

  Limitations

  Animal models; FOXO4-DRI tested in one mouse model only. A safety signal against senolytics in this context.

  DOI 10.1161/CIRCULATIONAHA.122.058794PubMed 36515093
• ✓ Positive animalAging (Albany NY) · 2020

  FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.

  Humans + animals

  In vitro and in vivo study of FOXO4-DRI

  In naturally aged mice, FOXO4-DRI removed senescent Leydig cells, improved the testicular microenvironment and alleviated age-related testosterone insufficiency.

  Study details

  Studied

  Human testis tissue, H2O2-induced senescent TM3 Leydig cells, and naturally aged mice

  Main outcome

  Senescent Leydig cell apoptosis; testicular microenvironment; testosterone secretion

  Authors' conclusion

  FOXO4-DRI selectively induced apoptosis in senescent Leydig cells and, in naturally aged mice, improved the testicular microenvironment and alleviated testosterone insufficiency, suggesting therapeutic potential.

  Limitations

  Cell and mouse data only; numbers not in the abstract.

  DOI 10.18632/aging.102682PubMed 31959736Free full text
  Figure 6
• ✓ Positive animalExp Gerontol · 2024

  FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.

  Humans + animals

  In vitro and in vivo study of FOXO4-DRI

  In naturally aged mice, FOXO4-DRI reduced senescent Leydig cell secretions and improved sperm quality and spermatogenesis.

  Study details

  Studied

  Senescent Leydig cells, co-cultured GC-1 SPG cells and naturally aged mice

  Main outcome

  SASP secretion, sperm quality, spermatogenesis

  Authors' conclusion

  FOXO4-DRI induced apoptosis in senescent Leydig cells, reduced certain SASP secretion and, in naturally aged mice, improved sperm quality and spermatogenesis.

  Limitations

  Cell and mouse data only; numbers not in the abstract.

  DOI 10.1016/j.exger.2024.112522PubMed 39025385
• ✓ Positive animalJ Cell Mol Med · 2022

  FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway.

  Humans + animals

  Mouse model comparing FOXO4-DRI with pirfenidone, plus in vitro myofibroblast assays

  In a bleomycin lung-fibrosis mouse model, FOXO4-DRI reduced senescent cells and collagen deposition, comparable to the approved drug pirfenidone.

  Study details

  Studied

  Bleomycin-induced pulmonary fibrosis mouse model; mouse and human lung fibroblast cell lines

  Compared with

  Pirfenidone

  Main outcome

  Senescent cells, SASP, morphology and collagen deposition

  Authors' conclusion

  Like pirfenidone, FOXO4-DRI decreased senescent cells and collagen deposition and reduced myofibroblasts; the authors suggest it may be a viable therapeutic option for pulmonary fibrosis.

  Limitations

  Mouse and cell-line study; numbers not in the abstract.

  DOI 10.1111/jcmm.17333PubMed 35510614Free full text
  FIGURE 1
• ~ Mixed in vitroFront Bioeng Biotechnol · 2021

  Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.

  Cells / lab

  In vitro treatment of expanded chondrocytes followed by pellet culture

  In expanded human chondrocytes, FOXO4-DRI removed over half of late-passage (senescent) cells but did not improve their cartilage-forming potential.

  Study details

  Studied

  Expanded human chondrocytes from healthy donors (population doubling level 3 and 9)

  Compared with

  Untreated chondrocytes; minimally expanded PDL3 cells

  Main outcome

  Cell number, senescence level, chondrogenic potential

  Authors' conclusion

  FOXO4-DRI removed more than half of PDL9 cells and reduced senescence, but did not enhance chondrogenic potential; its utility for cartilage formation needs further investigation.

  Limitations

  In vitro only; no benefit on cartilage formation shown.

  DOI 10.3389/fbioe.2021.677576PubMed 33996787Free full text
  FIGURE 2
• ✓ Positive in vitroMol Carcinog · 2026

  Acylglycerol Kinase Sensitizes Glioblastoma to Temozolomide via Limiting Mitochondrial Damage Related Cellular Senescence.

  Cells / lab

  In vitro cell experiments (plus TCGA data analysis)

  In glioblastoma cell experiments, FOXO4-DRI used as a senolytic cleared temozolomide-induced senescent cells by apoptosis and enhanced temozolomide's effect; the peptide was a tool in a study mainly about acylglycerol kinase.

  Study details

  Studied

  Glioblastoma cell lines treated with temozolomide

  Compared with

  Mito-TEMPO

  Main outcome

  Senescence, apoptosis and temozolomide efficacy

  Authors' conclusion

  FOXO4-DRI and Mito-TEMPO enhanced temozolomide efficacy by eliminating senescent cells via apoptosis; co-targeting AGK and senescence may be a strategy.

  Limitations

  Cell culture; FOXO4-DRI was a secondary tool, not the study focus.

  DOI 10.1002/mc.70134PubMed 42391447Free full text

Reported side effects

No human safety or efficacy data exist in the published literature; mouse data suggest senolytic clearance may harm pulmonary vascular function in some settings.

✓ positive · ✗ negative · ~ mixed · ? inconclusive, judged on each paper's own main outcome. Grades: A strong human evidence → D little or none. Papers and verdicts are drawn from PubMed, Europe PMC and Russian journals (CyberLeninka); not medical advice.