FOXO4-DRI

updated

FOXO4-DRI is a D-retro-inverso peptide designed to disrupt the interaction of FOXO4 with p53. A 2017 paper reported that it cleared senescent cells in culture and restored fitness, fur density and renal function in mice. No controlled human study exists: ClinicalTrials.gov queries on 9 October 2026 returned no studies, and in expanded human cartilage cells in a dish it removed more than half of the cells without improving the tissue outcome.

FOXO4-p53 interaction-disrupting peptide

  • PubChem lists FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two records (CID 167312269, labeled TFA salt form, and CID 168431240) whose stereochemistry is not identical.
  • DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation.
  • The 2017 paper reported restored fitness, fur density and renal function in fast-aging XpdTTD/TTD mice and naturally aged mice; it reports no human exposure and no pharmacokinetic parameter.
  • In expanded chondrocytes from healthy human donors, FOXO4-DRI removed more than half of the cells at population doubling level 9 and lowered senescence, but did not enhance chondrogenic potential.
  • In a pulmonary hypertension study, pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in mice given FOXO4-DRI or ABT263 compared with relevant controls.
  • ClinicalTrials.gov queries on 9 October 2026 for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies, and a PubMed search restricted to the humans MeSH term returned 9 records, none a human administration study.

What is FOXO4-DRI, and is it approved for anything?

FOXO4-DRI is a D-retro-inverso peptide, built from D-amino acids in reversed sequence, designed to disrupt the interaction of FOXO4 with p53. No approval for any use appears in the records reviewed, and ClinicalTrials.gov queries on 9 October 2026 returned no studies.

PubChem returns FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two records: CID 167312269, labeled FOXO4-DRI TFA salt form, and CID 168431240, labeled FOXO4-DRI. DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation. The stereochemistry in the two PubChem entries is not identical, and the TFA salt form is a distinct material from the free peptide.

ClinicalTrials.gov queries on 9 October 2026 for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies. A PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records, none a human administration study. No approval for any use appears in the records reviewed.

PubChem: FOXO4-DRI identity, two records, D-retro-inverso design

Chemical identity record

National Library of Medicine. PubChem compound records CID 167312269 (labeled FOXO4-DRI TFA salt form) and CID 168431240 (labeled FOXO4-DRI).

PubChem returns FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two CIDs: 167312269, labeled FOXO4-DRI TFA salt form, and 168431240, labeled FOXO4-DRI. DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation, and the stereochemistry in the two PubChem entries is not identical.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined D-retro-inverso peptide; TFA salt and non-salt records
Follow-up
Not applicable
Study design
NLM chemical records
Funding
not stated in the source

A 5358 Da all-D peptide is a different manufacturing and analysis problem from a short L-peptide, and the TFA salt form is a distinct material from the free peptide. The link is to the TFA salt record.

Read the original source
Searches, 9 October 2026: no registered study, no human administration study

PubMed search record

PubMed search run on 9 October 2026: FOXO4-DRI restricted to the humans MeSH term, 9 records. ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 run the same day.

ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies. A PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records: a mechanism paper, the keloid fibroblast study, the human chondrocyte study, the bronchopulmonary dysplasia study, two reviews, a lung cancer radiosensitization study, a glioblastoma study and the 2026 brain aging review. None is a human administration study. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for FOXO4-DRI, nine years after the 2017 paper.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

What have cell and mouse studies found?

In senescent cells FOXO4-DRI caused p53 nuclear exclusion and apoptosis, and in a 2017 paper it restored fitness, fur density and renal function in fast-aging and naturally aged mice. A second lab reported a consistent effect on testosterone secretion in aged mice.

The 2017 paper is the study the whole category rests on. The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

The paper reports mouse and cell results. It contains no human exposure, and its abstract reports no pharmacokinetic parameter. The fitness, fur density and renal function results have not been independently repeated in the records reviewed.

A different lab found that FOXO4 is expressed in human Leydig cells, with nuclear translocation in the elderly related to decreased testosterone synthesis. In hydrogen peroxide-induced senescent TM3 Leydig cells, FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis, and in naturally aged mice it improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. That is a consistent result in a narrow tissue.

The papers in this section do not state a route or dose in the information reviewed, so none is given here.

2017 founding paper: senescent cells and aged mice, no human exposure

Animal study

Baar MP et al. Cell. 2017;169(1):132-147.e16. PMID 28340339.

The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

Participants / model
Cultured senescent cells; XpdTTD/TTD fast-aging mice; naturally aged mice; doxorubicin-treated mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The paper reports mouse and cell results. It contains no human exposure, and the abstract reports no pharmacokinetic parameter. The 2017 fitness, fur density and renal function results have not been independently repeated in the records reviewed.

Read the original source
Independent follow-up: Leydig cells and aged mice, testosterone secretion

Animal study

Zhang C et al. Aging (Albany NY). 2020;12(2):1272-1284. PMID 31959736.

FOXO4 was found expressed in human Leydig cells with nuclear translocation in the elderly related to decreased testosterone synthesis. In hydrogen peroxide-induced senescent TM3 Leydig cells, FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency.

Participants / model
Human Leydig cell tissue for expression; TM3 mouse Leydig cells; naturally aged mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study from a different lab than the 2017 group
Funding
not stated in the source

A consistent result in a narrow tissue. The human material was used to show FOXO4 expression, not to give anyone the peptide.

Read the original source

What happened when FOXO4-DRI was applied to donor cartilage cells?

In expanded chondrocytes from healthy human donors it removed more than half of the cells at population doubling level 9 and lowered senescence, but did not improve the cartilage-forming potential of the cells. The cells were treated in a dish.

Chondrocytes isolated from healthy human donors were expanded to population doubling level 9, representing cells ready for autologous chondrocyte implantation, with level 3 cells as a minimally expanded control. FOXO4-DRI removed more than half of the cells at level 9 and did not significantly affect cell number at level 3, and the senescence level in treated level 9 chondrocytes was significantly reduced.

However, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of level 9 chondrocytes. The cartilage generated from treated cells only showed lower expression of senescence-relevant secretory factors. Clearing the senescent cells did not improve the tissue outcome in this experiment.

This is the closest thing to a human result, and it is cells in a dish. No person received the peptide.

Human donor chondrocytes in a dish: more than half removed, tissue outcome not improved

Cell study

Huang Y et al. Front Bioeng Biotechnol. 2021;9:677576. PMID 33996787.

Chondrocytes isolated from healthy human donors were expanded to population doubling level 9, representing cells ready for autologous chondrocyte implantation, with population doubling level 3 cells as a minimally expanded control. FOXO4-DRI removed more than half of the cells at population doubling level 9 and did not significantly affect cell number at level 3, and the senescence level in treated level 9 chondrocytes was significantly reduced. However, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of level 9 chondrocytes; the cartilage generated from treated cells only showed lower expression of senescence-relevant secretory factors.

Participants / model
Human chondrocytes from healthy donors, expanded in vitro
Treatment
FOXO4-DRI applied to cultured cells
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the closest thing to a human result, and it is cells in a dish. Clearing the senescent cells did not improve the tissue outcome in this experiment.

Read the original source

Did removing senescent cells ever worsen an outcome in animals?

Yes, in a pulmonary hypertension study. Pulmonary hemodynamic alterations and loss of lung endothelial cells occurred in mice given FOXO4-DRI or the senolytic ABT263, and the authors concluded that eliminating senescent pulmonary endothelial cells may worsen hemodynamics. This is a mouse and rat result.

A study of senescent cells in pulmonary hypertension used several senolytic approaches: a suicide gene construct, ABT263 and the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI. Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling and markedly decreased lung endothelial cells.

Pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI compared with relevant controls. In rats, monocrotaline-induced pulmonary hypertension was slightly reduced by ABT263 at 1 week but aggravated at 3 weeks. The published conclusion was that eliminating senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary hemodynamics.

This is a finding in mice and rats. It is not a measured risk in people, and patient samples in the study were used for marker analysis, not to give anyone the peptide.

Pulmonary hypertension models: senolytic removal of endothelial cells worsened hemodynamics

Animal study

Born E et al. Circulation. 2023;147(8):650-666. PMID 36515093.

A study of senescent cells in pulmonary hypertension used several senolytic approaches, including a suicide gene construct, ABT263, and the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI. Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling, and markedly decreased lung pulmonary endothelial cells. Pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI compared with relevant controls. In rats, monocrotaline-induced pulmonary hypertension was slightly reduced by ABT263 at 1 week but aggravated at 3 weeks. The published conclusion was that eliminating senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary hemodynamics.

Participants / model
Patients with pulmonary arterial hypertension for the marker analysis; several mouse strains; rats given monocrotaline
Treatment
FOXO4-DRI and ABT263 as dosed in the report; route not stated in the information reviewed
Follow-up
Rat monocrotaline results at 1 and 3 weeks
Study design
Original preclinical study
Funding
not stated in the source

This is a mouse and rat result, not a measured human risk. The patient samples were used for marker analysis, and no patient received the peptide.

Read the original source

Does clearing senescent cells deliver the benefits sellers describe?

Senescent cell clearance is supported in mouse models and in human cells in culture. The claims about inflammation, tissue dysfunction and regeneration rest on a single 2017 mouse paper, and in the one experiment that tested a regeneration outcome, in human chondrocytes, clearance did not improve it.

Sellers describe FOXO4-DRI as a senolytic therapy that clears senescent cells driving inflammation, tissue dysfunction and poor regeneration with age.

Senescent cell clearance is supported in mouse models and in human cells in culture. The downstream claims about inflammation, tissue dysfunction and regeneration rest on a single 2017 mouse paper. In the one experiment that tested whether clearance improved a regeneration outcome, expanded human chondrocytes, it did not.

A 2026 narrative review of the FOXO4-p53 axis in brain aging describes FOXO4-DRI reducing senescent cell accumulation, restoring cerebral blood flow and blood-brain barrier integrity, reversing hippocampal atrophy and improving cognition in aged mammalian models. Where it turns to human data, the preliminary human studies it cites are of FOXO4-axis modulators such as high-dose fisetin, not FOXO4-DRI. The review records no human study of the peptide itself.

ClinicalTrials.gov queries on 9 October 2026 returned no studies, and a PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records, none a human administration study, nine years after the 2017 paper.

2017 founding paper: senescent cells and aged mice, no human exposure

Animal study

Baar MP et al. Cell. 2017;169(1):132-147.e16. PMID 28340339.

The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

Participants / model
Cultured senescent cells; XpdTTD/TTD fast-aging mice; naturally aged mice; doxorubicin-treated mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The paper reports mouse and cell results. It contains no human exposure, and the abstract reports no pharmacokinetic parameter. The 2017 fitness, fur density and renal function results have not been independently repeated in the records reviewed.

Read the original source
Human donor chondrocytes in a dish: more than half removed, tissue outcome not improved

Cell study

Huang Y et al. Front Bioeng Biotechnol. 2021;9:677576. PMID 33996787.

Chondrocytes isolated from healthy human donors were expanded to population doubling level 9, representing cells ready for autologous chondrocyte implantation, with population doubling level 3 cells as a minimally expanded control. FOXO4-DRI removed more than half of the cells at population doubling level 9 and did not significantly affect cell number at level 3, and the senescence level in treated level 9 chondrocytes was significantly reduced. However, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of level 9 chondrocytes; the cartilage generated from treated cells only showed lower expression of senescence-relevant secretory factors.

Participants / model
Human chondrocytes from healthy donors, expanded in vitro
Treatment
FOXO4-DRI applied to cultured cells
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the closest thing to a human result, and it is cells in a dish. Clearing the senescent cells did not improve the tissue outcome in this experiment.

Read the original source
2026 narrative review: animal models only, human studies cited are of other compounds

Narrative review

Alameen AAM et al. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(10):14659-14676. PMID 42024235.

A narrative review of the FOXO4-p53 axis in brain aging describes FOXO4-DRI reducing senescent cell accumulation, restoring cerebral blood flow and blood-brain barrier integrity, reversing hippocampal atrophy, and improving cognition in aged mammalian models, and clearing amyloid-beta and pathological tau in Alzheimer and tauopathy models. Where it turns to human data, the preliminary human studies it cites are of FOXO4-axis modulators such as high-dose fisetin, not FOXO4-DRI. The review records no human study of the peptide itself.

Participants / model
Animal models as reviewed; human studies cited are of a different compound
Treatment
Narrative review, no new exposure
Follow-up
Not applicable
Study design
Narrative review
Funding
not stated in the source

The review's preliminary human studies refer to fisetin and are not attributed to this peptide.

Read the original source
Searches, 9 October 2026: no registered study, no human administration study

PubMed search record

PubMed search run on 9 October 2026: FOXO4-DRI restricted to the humans MeSH term, 9 records. ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 run the same day.

ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies. A PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records: a mechanism paper, the keloid fibroblast study, the human chondrocyte study, the bronchopulmonary dysplasia study, two reviews, a lung cancer radiosensitization study, a glioblastoma study and the 2026 brain aging review. None is a human administration study. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for FOXO4-DRI, nine years after the 2017 paper.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

How does FOXO4-DRI work?

FOXO4-DRI is designed to perturb the interaction of FOXO4 with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. No half-life or exposure figure exists for any species.

The 2017 authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis, and a different lab reproduced p53 nuclear exclusion and apoptosis in hydrogen peroxide-induced senescent TM3 Leydig cells.

The D-retro-inverso design, D-amino acids in reversed sequence, is used to resist protease degradation.

No pharmacokinetic figure exists for any species in the records reviewed, so no half-life or dosing interval is given. The 2017 abstract reports no pharmacokinetic parameter.

2017 founding paper: senescent cells and aged mice, no human exposure

Animal study

Baar MP et al. Cell. 2017;169(1):132-147.e16. PMID 28340339.

The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

Participants / model
Cultured senescent cells; XpdTTD/TTD fast-aging mice; naturally aged mice; doxorubicin-treated mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The paper reports mouse and cell results. It contains no human exposure, and the abstract reports no pharmacokinetic parameter. The 2017 fitness, fur density and renal function results have not been independently repeated in the records reviewed.

Read the original source
Independent follow-up: Leydig cells and aged mice, testosterone secretion

Animal study

Zhang C et al. Aging (Albany NY). 2020;12(2):1272-1284. PMID 31959736.

FOXO4 was found expressed in human Leydig cells with nuclear translocation in the elderly related to decreased testosterone synthesis. In hydrogen peroxide-induced senescent TM3 Leydig cells, FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency.

Participants / model
Human Leydig cell tissue for expression; TM3 mouse Leydig cells; naturally aged mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study from a different lab than the 2017 group
Funding
not stated in the source

A consistent result in a narrow tissue. The human material was used to show FOXO4 expression, not to give anyone the peptide.

Read the original source
PubChem: FOXO4-DRI identity, two records, D-retro-inverso design

Chemical identity record

National Library of Medicine. PubChem compound records CID 167312269 (labeled FOXO4-DRI TFA salt form) and CID 168431240 (labeled FOXO4-DRI).

PubChem returns FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two CIDs: 167312269, labeled FOXO4-DRI TFA salt form, and 168431240, labeled FOXO4-DRI. DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation, and the stereochemistry in the two PubChem entries is not identical.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined D-retro-inverso peptide; TFA salt and non-salt records
Follow-up
Not applicable
Study design
NLM chemical records
Funding
not stated in the source

A 5358 Da all-D peptide is a different manufacturing and analysis problem from a short L-peptide, and the TFA salt form is a distinct material from the free peptide. The link is to the TFA salt record.

Read the original source

What risks and unknowns do the studies show?

No human dose, pharmacokinetics or safety data exist. In a pulmonary hypertension study, pulmonary endothelial cell loss and hemodynamic alterations occurred in mice given FOXO4-DRI, a mouse and rat result and not a measured human risk.

The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for FOXO4-DRI.

In a study of pulmonary hypertension, pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given FOXO4-DRI or ABT263 compared with relevant controls, and the authors concluded that eliminating senescent pulmonary endothelial cells may worsen pulmonary hemodynamics. This is a mouse and rat result, not a measured human risk.

PubChem carries two FOXO4-DRI records, one labeled as a TFA salt form, with non-identical stereochemistry, so the identity of a given vial depends on which material it is. No pharmacokinetic figure exists for any species.

Searches, 9 October 2026: no registered study, no human administration study

PubMed search record

PubMed search run on 9 October 2026: FOXO4-DRI restricted to the humans MeSH term, 9 records. ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 run the same day.

ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies. A PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records: a mechanism paper, the keloid fibroblast study, the human chondrocyte study, the bronchopulmonary dysplasia study, two reviews, a lung cancer radiosensitization study, a glioblastoma study and the 2026 brain aging review. None is a human administration study. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for FOXO4-DRI, nine years after the 2017 paper.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source
Pulmonary hypertension models: senolytic removal of endothelial cells worsened hemodynamics

Animal study

Born E et al. Circulation. 2023;147(8):650-666. PMID 36515093.

A study of senescent cells in pulmonary hypertension used several senolytic approaches, including a suicide gene construct, ABT263, and the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI. Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling, and markedly decreased lung pulmonary endothelial cells. Pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI compared with relevant controls. In rats, monocrotaline-induced pulmonary hypertension was slightly reduced by ABT263 at 1 week but aggravated at 3 weeks. The published conclusion was that eliminating senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary hemodynamics.

Participants / model
Patients with pulmonary arterial hypertension for the marker analysis; several mouse strains; rats given monocrotaline
Treatment
FOXO4-DRI and ABT263 as dosed in the report; route not stated in the information reviewed
Follow-up
Rat monocrotaline results at 1 and 3 weeks
Study design
Original preclinical study
Funding
not stated in the source

This is a mouse and rat result, not a measured human risk. The patient samples were used for marker analysis, and no patient received the peptide.

Read the original source
PubChem: FOXO4-DRI identity, two records, D-retro-inverso design

Chemical identity record

National Library of Medicine. PubChem compound records CID 167312269 (labeled FOXO4-DRI TFA salt form) and CID 168431240 (labeled FOXO4-DRI).

PubChem returns FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two CIDs: 167312269, labeled FOXO4-DRI TFA salt form, and 168431240, labeled FOXO4-DRI. DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation, and the stereochemistry in the two PubChem entries is not identical.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined D-retro-inverso peptide; TFA salt and non-salt records
Follow-up
Not applicable
Study design
NLM chemical records
Funding
not stated in the source

A 5358 Da all-D peptide is a different manufacturing and analysis problem from a short L-peptide, and the TFA salt form is a distinct material from the free peptide. The link is to the TFA salt record.

Read the original source

Why does FOXO4-DRI sit in C tier?

The mechanism is real and the senolytic effect has been reproduced in narrow settings, but the headline mouse results rest on one 2017 paper, no human has received the peptide, and clearing cells did not improve a tissue outcome in human chondrocytes.

The 2017 paper is real work with a real mechanism, and the senolytic effect has been reproduced by other labs in narrow settings, including aged mouse Leydig cells and expanded human chondrocytes. None of that is replication of the headline claim. The 2017 fitness, fur density and renal function results in aged mice have not been independently repeated in the records reviewed, and there is no registered clinical trial and no human dose nine years on.

A pulmonary hypertension study found worse hemodynamics in mice after elimination of senescent endothelial cells, including with FOXO4-DRI. The human chondrocyte study is instructive: the peptide did clear more than half the senescent cells and did not improve the tissue outcome.

2017 founding paper: senescent cells and aged mice, no human exposure

Animal study

Baar MP et al. Cell. 2017;169(1):132-147.e16. PMID 28340339.

The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

Participants / model
Cultured senescent cells; XpdTTD/TTD fast-aging mice; naturally aged mice; doxorubicin-treated mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The paper reports mouse and cell results. It contains no human exposure, and the abstract reports no pharmacokinetic parameter. The 2017 fitness, fur density and renal function results have not been independently repeated in the records reviewed.

Read the original source
Independent follow-up: Leydig cells and aged mice, testosterone secretion

Animal study

Zhang C et al. Aging (Albany NY). 2020;12(2):1272-1284. PMID 31959736.

FOXO4 was found expressed in human Leydig cells with nuclear translocation in the elderly related to decreased testosterone synthesis. In hydrogen peroxide-induced senescent TM3 Leydig cells, FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency.

Participants / model
Human Leydig cell tissue for expression; TM3 mouse Leydig cells; naturally aged mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study from a different lab than the 2017 group
Funding
not stated in the source

A consistent result in a narrow tissue. The human material was used to show FOXO4 expression, not to give anyone the peptide.

Read the original source
Human donor chondrocytes in a dish: more than half removed, tissue outcome not improved

Cell study

Huang Y et al. Front Bioeng Biotechnol. 2021;9:677576. PMID 33996787.

Chondrocytes isolated from healthy human donors were expanded to population doubling level 9, representing cells ready for autologous chondrocyte implantation, with population doubling level 3 cells as a minimally expanded control. FOXO4-DRI removed more than half of the cells at population doubling level 9 and did not significantly affect cell number at level 3, and the senescence level in treated level 9 chondrocytes was significantly reduced. However, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of level 9 chondrocytes; the cartilage generated from treated cells only showed lower expression of senescence-relevant secretory factors.

Participants / model
Human chondrocytes from healthy donors, expanded in vitro
Treatment
FOXO4-DRI applied to cultured cells
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the closest thing to a human result, and it is cells in a dish. Clearing the senescent cells did not improve the tissue outcome in this experiment.

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Pulmonary hypertension models: senolytic removal of endothelial cells worsened hemodynamics

Animal study

Born E et al. Circulation. 2023;147(8):650-666. PMID 36515093.

A study of senescent cells in pulmonary hypertension used several senolytic approaches, including a suicide gene construct, ABT263, and the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI. Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling, and markedly decreased lung pulmonary endothelial cells. Pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI compared with relevant controls. In rats, monocrotaline-induced pulmonary hypertension was slightly reduced by ABT263 at 1 week but aggravated at 3 weeks. The published conclusion was that eliminating senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary hemodynamics.

Participants / model
Patients with pulmonary arterial hypertension for the marker analysis; several mouse strains; rats given monocrotaline
Treatment
FOXO4-DRI and ABT263 as dosed in the report; route not stated in the information reviewed
Follow-up
Rat monocrotaline results at 1 and 3 weeks
Study design
Original preclinical study
Funding
not stated in the source

This is a mouse and rat result, not a measured human risk. The patient samples were used for marker analysis, and no patient received the peptide.

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Searches, 9 October 2026: no registered study, no human administration study

PubMed search record

PubMed search run on 9 October 2026: FOXO4-DRI restricted to the humans MeSH term, 9 records. ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 run the same day.

ClinicalTrials.gov queries for FOXO4-DRI, FOXO4 senolytic and senolytic peptide FOXO4 returned no studies. A PubMed search for FOXO4-DRI restricted to the humans MeSH term returned 9 records: a mechanism paper, the keloid fibroblast study, the human chondrocyte study, the bronchopulmonary dysplasia study, two reviews, a lung cancer radiosensitization study, a glioblastoma study and the 2026 brain aging review. None is a human administration study. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for FOXO4-DRI, nine years after the 2017 paper.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

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Studies and sources

PubChem: FOXO4-DRI identity, two records, D-retro-inverso design

Chemical identity record

National Library of Medicine. PubChem compound records CID 167312269 (labeled FOXO4-DRI TFA salt form) and CID 168431240 (labeled FOXO4-DRI).

PubChem returns FOXO4-DRI as C228H388N86O64, molecular weight 5358, CAS 2460055-10-9, under two CIDs: 167312269, labeled FOXO4-DRI TFA salt form, and 168431240, labeled FOXO4-DRI. DRI stands for D-retro-inverso: the peptide is built from D-amino acids in reversed sequence, a design used to resist protease degradation, and the stereochemistry in the two PubChem entries is not identical.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined D-retro-inverso peptide; TFA salt and non-salt records
Follow-up
Not applicable
Study design
NLM chemical records
Funding
not stated in the source

A 5358 Da all-D peptide is a different manufacturing and analysis problem from a short L-peptide, and the TFA salt form is a distinct material from the free peptide. The link is to the TFA salt record.

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2017 founding paper: senescent cells and aged mice, no human exposure

Animal study

Baar MP et al. Cell. 2017;169(1):132-147.e16. PMID 28340339.

The authors identified FOXO4 as a pivot in senescent cell viability and designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells this selectively caused p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, the peptide neutralized doxorubicin-induced chemotoxicity, and it restored fitness, fur density and renal function in both fast-aging XpdTTD/TTD mice and naturally aged mice.

Participants / model
Cultured senescent cells; XpdTTD/TTD fast-aging mice; naturally aged mice; doxorubicin-treated mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

The paper reports mouse and cell results. It contains no human exposure, and the abstract reports no pharmacokinetic parameter. The 2017 fitness, fur density and renal function results have not been independently repeated in the records reviewed.

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Independent follow-up: Leydig cells and aged mice, testosterone secretion

Animal study

Zhang C et al. Aging (Albany NY). 2020;12(2):1272-1284. PMID 31959736.

FOXO4 was found expressed in human Leydig cells with nuclear translocation in the elderly related to decreased testosterone synthesis. In hydrogen peroxide-induced senescent TM3 Leydig cells, FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency.

Participants / model
Human Leydig cell tissue for expression; TM3 mouse Leydig cells; naturally aged mice
Treatment
FOXO4-DRI as dosed in the report; route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study from a different lab than the 2017 group
Funding
not stated in the source

A consistent result in a narrow tissue. The human material was used to show FOXO4 expression, not to give anyone the peptide.

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Human donor chondrocytes in a dish: more than half removed, tissue outcome not improved

Cell study

Huang Y et al. Front Bioeng Biotechnol. 2021;9:677576. PMID 33996787.

Chondrocytes isolated from healthy human donors were expanded to population doubling level 9, representing cells ready for autologous chondrocyte implantation, with population doubling level 3 cells as a minimally expanded control. FOXO4-DRI removed more than half of the cells at population doubling level 9 and did not significantly affect cell number at level 3, and the senescence level in treated level 9 chondrocytes was significantly reduced. However, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of level 9 chondrocytes; the cartilage generated from treated cells only showed lower expression of senescence-relevant secretory factors.

Participants / model
Human chondrocytes from healthy donors, expanded in vitro
Treatment
FOXO4-DRI applied to cultured cells
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the closest thing to a human result, and it is cells in a dish. Clearing the senescent cells did not improve the tissue outcome in this experiment.

Read the original source
Pulmonary hypertension models: senolytic removal of endothelial cells worsened hemodynamics

Animal study

Born E et al. Circulation. 2023;147(8):650-666. PMID 36515093.

A study of senescent cells in pulmonary hypertension used several senolytic approaches, including a suicide gene construct, ABT263, and the cell-permeable FOXO4-p53 interfering peptide FOXO4-DRI. Senescent cell elimination by suicide gene or ABT263 increased right ventricular systolic pressure and the hypertrophy index, increased vessel remodeling, and markedly decreased lung pulmonary endothelial cells. Pulmonary hemodynamic alterations and pulmonary endothelial cell loss occurred in SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI compared with relevant controls. In rats, monocrotaline-induced pulmonary hypertension was slightly reduced by ABT263 at 1 week but aggravated at 3 weeks. The published conclusion was that eliminating senescent pulmonary endothelial cells by senolytic interventions may worsen pulmonary hemodynamics.

Participants / model
Patients with pulmonary arterial hypertension for the marker analysis; several mouse strains; rats given monocrotaline
Treatment
FOXO4-DRI and ABT263 as dosed in the report; route not stated in the information reviewed
Follow-up
Rat monocrotaline results at 1 and 3 weeks
Study design
Original preclinical study
Funding
not stated in the source

This is a mouse and rat result, not a measured human risk. The patient samples were used for marker analysis, and no patient received the peptide.

Read the original source
2026 narrative review: animal models only, human studies cited are of other compounds

Narrative review

Alameen AAM et al. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(10):14659-14676. PMID 42024235.

A narrative review of the FOXO4-p53 axis in brain aging describes FOXO4-DRI reducing senescent cell accumulation, restoring cerebral blood flow and blood-brain barrier integrity, reversing hippocampal atrophy, and improving cognition in aged mammalian models, and clearing amyloid-beta and pathological tau in Alzheimer and tauopathy models. Where it turns to human data, the preliminary human studies it cites are of FOXO4-axis modulators such as high-dose fisetin, not FOXO4-DRI. The review records no human study of the peptide itself.

Participants / model
Animal models as reviewed; human studies cited are of a different compound
Treatment
Narrative review, no new exposure
Follow-up
Not applicable
Study design
Narrative review
Funding
not stated in the source

The review's preliminary human studies refer to fisetin and are not attributed to this peptide.

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Why is FOXO4-DRI in C tier?

C fits a peptide with a real mechanism and consistent senolytic results in cells and mice, and no human administration. The 2017 fitness, fur density and kidney results rest on one mouse paper, no trial or human dose exists nine years on, and in the one experiment that tested a regeneration outcome in human cells, clearing senescent cells did not improve it.