FOXO4-DRI Research Dosing: Every Published Protocol (2026)
Summary
There is no human FOXO4-DRI dose, because the peptide has never been tested in people. The animal literature is unusually consistent, though: nearly every published in vivo study used 5 mg/kg per injection, given three times on alternate days (days 1, 3, and 5, or days 14, 16, and 18 in the pulmonary fibrosis model), with effects tracked over the following three to four weeks. In cell culture, 25 μM applied for three to five days is the standard working concentration. Everything below is drawn from the published studies themselves; anything you read elsewhere that goes further is extrapolation, not evidence.
Key Data
Never tested in humans (as of July 2026)
Three alternate-day injections
3–5 days exposure
No oral or subcutaneous data published
Readouts 21–30 days after first dose
Why There Is No Human Dose
Search for FOXO4-DRI dosing online and you will find vendor pages and forums quoting human microgram-per-kilogram "protocols" down to the decimal. None of them cite a human study, for a simple reason: there isn't one. As of July 2026, FOXO4-DRI has never been administered to a person in any registered or published trial, and ClinicalTrials.gov returns zero studies for the compound.
Two kinds of data are missing before anyone could propose a human dose honestly. First, pharmacokinetics: nobody has measured FOXO4-DRI's half-life, tissue distribution, or clearance in any species, so there is no exposure curve to scale from. Second, formal toxicology: the only safety information available is the absence of obvious problems in small groups of mice at a single regimen. A first-in-human starting dose is normally derived from animal no-observed-adverse-effect levels combined with PK modeling. Neither input exists here.
We therefore do not publish a mouse-to-human conversion on this page. Allometric calculators are easy to find, and running 5 mg/kg through one produces a confident-looking number. But it would be a number built on unknowns, presented as if it were a finding. On a topic where people inject themselves based on what websites say, that is not a calculation we are willing to dress up as guidance.
The Mouse Protocols, Study by Study
Three in vivo studies report their FOXO4-DRI regimens in enough detail to quote directly, and they converge on the same schedule.
Baar et al. 2017 (PMID 28340339). The founding study used 5 mg/kg per injection, three injections on alternate days (days 1, 3, and 5). In the doxorubicin arm, where mice first received two 10 mg/kg intraperitoneal doses of doxorubicin to induce senescence, FOXO4-DRI was given intravenously. In the fast-aging Xpd and naturally aged experiments it was given intraperitoneally. Outcomes (fur, activity, renal markers, senescent-cell burden) were followed for roughly 30 days after the three-dose series.
Zhang et al. 2020 (PMID 31959736). Aged male mice (20–24 months) received 5 mg/kg intraperitoneally every other day for three administrations; testosterone and testicular markers were measured 30 days later. Body weight and testis weight were unchanged by treatment.
Han et al. 2022 (PMID 35510614). In a bleomycin pulmonary fibrosis model (5 mg/kg bleomycin by intratracheal instillation on day 0), FOXO4-DRI was dosed at 5 mg/kg intraperitoneally on days 14, 16, and 18, with analysis on day 21. The comparison arm received pirfenidone 300 mg/kg across 20 administrations, meaning the approved antifibrotic needed roughly seven times as many dosing events to reach a comparable effect in this model.
Later studies. Liu et al. 2023 (bleomycin fibrosis, PMID 37074394) and Li et al. 2024 (aged-mouse spermatogenesis, PMID 39025385) both dosed mice with FOXO4-DRI, but their abstracts do not state the regimen and the full texts are paywalled; we cite them without quoting a dose rather than guess. Meng et al. 2021 (PMID 34877934) used FOXO4-DRI in mouse lung-cancer radiotherapy models.
The pattern across the verifiable protocols is hard to miss: 5 mg/kg, three alternate-day injections, then watch for a month. No dose-ranging study has been published in animals, so whether 5 mg/kg is optimal, sub-therapeutic, or excessive in mice is itself an open question.
Cell Culture Concentrations
In vitro work clusters around 25 μM:
- Baar 2017: 25 μM standard exposure (range tested 6.25–25 μM) on senescent human IMR90 fibroblasts. The selectivity index (SI50) quantified how much more potently the peptide killed senescent versus control cells.
- Huang et al. 2021 (PMID 33996787): 25 μM for 5 days in 2% FBS medium on osteoarthritic human chondrocytes, followed by 2–3 days of recovery before analysis.
- Kong et al. 2025 (PMID 39994346): 25 μM for 3 days on serum-starved keloid fibroblasts, and the same concentration in keloid organ cultures with readouts at days 0, 3, 7, and 10.
- Hu et al. 2025 (PMID 41625068): 50 μM on endothelial (HUVEC) cultures under hypoxia and glucose deprivation.
Han 2022 measured full potency curves rather than picking a single concentration: the IC50 against TGF-β-activated mouse lung fibroblasts fell from 145 μM at 24 hours to 13 μM at 72 hours, and the peptide preferentially killed activated myofibroblasts over resting fibroblasts — the in vitro version of the same selectivity Baar described in IMR90 cells.
Why Three Doses Instead of Daily
Everything about FOXO4-DRI dosing looks odd from a conventional pharmacology standpoint: no daily schedule, no steady state, no maintenance phase. It makes sense once the mechanism is clear. Senolytics do not suppress a pathway that needs continuous blockade. Instead, they kill the senescent cells present on the day of treatment, and because senescent cells take weeks to re-accumulate, a brief course buys a long effect. Wissler Gerdes et al. laid out this "hit-and-run" rationale and how it shapes senolytic trial design (PMID 34699859).
The human senolytic literature runs on the same logic. Hickson et al. 2019 gave dasatinib 100 mg plus quercetin 1,000 mg for three consecutive days in diabetic kidney disease (PMID 31542391). Justice et al. 2019 used dasatinib 100 mg/day plus quercetin 1,250 mg/day, three days per week for three weeks, in idiopathic pulmonary fibrosis (PMID 30616998). These are the only peer-reviewed human senolytic schedules in existence, and they are for a completely different drug pair. That is the point worth remembering: if a clinic claims to run a "FOXO4-DRI protocol," it was not derived from any published human work.
What a Real Human Protocol Would Require
The gap between a mouse regimen and a clinical one is not a calculation. It is a development program. The missing pieces, in order:
- Pharmacokinetics: half-life, exposure, and tissue distribution in at least one species.
- GLP toxicology: dose-escalation and repeat-dose studies under regulatory-grade conditions.
- A workable route: intravenous or subcutaneous. Intraperitoneal injection, the workhorse of the mouse studies, is not a standard systemic route in people.
- Manufacturing: FOXO4-DRI is a 46-amino-acid D-retro-inverso peptide (sequence disclosed in the Baar 2017 methods), and D-amino-acid synthesis at pharmaceutical grade is expensive. Rai reviewed why retro-inverso chemistry remains a production barrier (PMID 30582286).
Notably, the company spun out of the inventing lab is not advancing FOXO4-DRI itself. Cleara Biotech's pipeline lists optimized follow-on candidates (CL04177/CL04183) aimed at p53-impaired cancer cells, which it reports have a maximum tolerated dose well above their efficacious dose in mice. Even the originators are betting on second-generation molecules rather than the compound sold by research vendors today.
This page documents published research protocols for informational purposes. It is not dosing guidance for humans or animals, and self-administration of research peptides carries unknown risk.
Frequently Asked Questions
What dose of FOXO4-DRI was used in the research studies?
In mice, 5 mg/kg per injection, three injections on alternate days: that is the regimen reported in Baar 2017, Zhang 2020, and Han 2022. In cell culture, 25 μM for three to five days is the standard working concentration. No other regimens have been published in the peer-reviewed literature.
Is there a human FOXO4-DRI dosage?
No. FOXO4-DRI has never been tested in humans, so no human dose, safe or effective, has ever been established. Websites quoting human dosing are extrapolating from mouse data without the pharmacokinetic or toxicology data needed to do so responsibly.
How often was FOXO4-DRI injected in the mouse studies?
Three times total, every other day (days 1, 3, and 5, or days 14, 16, and 18 in the bleomycin fibrosis model). Not daily and not continuously: the peptide clears existing senescent cells, and the effect was then tracked for roughly a month.
Why do senolytics use intermittent dosing?
Senolytics kill the senescent cells present at treatment time rather than blocking a pathway continuously. Because new senescent cells take weeks to accumulate, brief courses spaced far apart achieve the effect with less total drug exposure. This 'hit-and-run' principle also guides the dasatinib+quercetin human trials.
Can FOXO4-DRI be taken orally?
No published study has used oral administration. All animal work used intravenous or intraperitoneal injection. Peptides of this size are poorly absorbed from the gut, and there is no oral bioavailability data of any kind for FOXO4-DRI.
Citations
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging
Baar MP, Brandt RMC, Putavet DA, et al.
Cell (2017)
The founding FOXO4-DRI study. Regimen: 5 mg/kg per injection on three alternate days — intravenous in the doxorubicin arm, intraperitoneal in the aging arms — with outcomes tracked ~30 days. In vitro standard: 25 μM (6.25–25 μM tested).
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice
Zhang C, Xie Y, Chen H, et al.
Aging (Albany NY) (2020)
Aged male mice (20–24 months) received 5 mg/kg intraperitoneally every other day for three administrations; testosterone measured 30 days later. Body weight and testis weight unchanged.
FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway
Han X, Yuan T, Zhang J, et al.
Journal of Cellular and Molecular Medicine (2022)
Bleomycin fibrosis model: 5 mg/kg i.p. on days 14, 16, and 18 post-bleomycin, analysis on day 21; pirfenidone 300 mg/kg ×20 as comparator. In vitro IC50 on activated myofibroblasts fell to 13 μM by 72 h, with preferential myofibroblast killing.
Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes
Huang Y, He Y, Makarcyzk MJ, Lin H
Frontiers in Bioengineering and Biotechnology (2021)
Human osteoarthritic chondrocytes treated with 25 μM FOXO4-DRI for 5 days in 2% FBS medium; selective removal of senescent cells while sparing non-senescent cells.
FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation
Kong YX, Li ZS, Liu YB, et al.
Communications Biology (2025)
25 μM FOXO4-DRI for 3 days cleared senescent keloid fibroblasts; keloid organ cultures treated at the same concentration showed apoptosis at days 3–10.
FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway
Hu Z, Li F, Hu C, et al.
Frontiers in Bioengineering and Biotechnology (2025)
Endothelial cell (HUVEC) senescence model under hypoxia/glucose deprivation treated with 50 μM FOXO4-DRI; effects mediated through the p53 pathway.
Strategies for Late Phase Preclinical and Early Clinical Trials of Senolytics
Wissler Gerdes EO, Misra A, Netto JME, et al.
Mechanisms of Ageing and Development (2021)
Review of senolytic trial design including the 'hit-and-run' intermittent dosing principle: kill existing senescent cells, then allow weeks before re-treatment.
Senolytics Decrease Senescent Cells in Humans: Preliminary Report from a Clinical Trial of Dasatinib plus Quercetin in Individuals with Diabetic Kidney Disease
Hickson LJ, Langhi Prata LG, Boez SA, et al.
EBioMedicine (2019)
First-in-human senolytic trial: dasatinib 100 mg + quercetin 1,000 mg for three consecutive days in diabetic kidney disease (N=9). The only peer-reviewed human senolytic schedules are for this drug pair, not FOXO4-DRI.
Senolytics in Idiopathic Pulmonary Fibrosis: Results from a First-in-Human, Open-Label, Pilot Study
Justice JN, Nambiar AM, Tchkonia T, et al.
EBioMedicine (2019)
IPF pilot (N=14): dasatinib 100 mg/day + quercetin 1,250 mg/day, three days per week for three weeks — the human reference schedule for intermittent senolytic dosing.