Foxo4 Dri: Safety Profile & Research Summary

Preclinical Research Summary

Key Preclinical Animal Studies

Study	Model	Key Findings	Ref
Baar et al. (2017) Cell	C57BL/6J mice — Doxorubicin chemotoxicity; 5 mg/kg i.v., 3 doses over 5 days	Neutralized plasma AST elevation (liver toxicity); prevented body weight loss; reduced IL-6 and FOXO4 foci in liver tissue	[1]
Baar et al. (2017) Cell	XpdTTD/TTD fast-aging mice; 5 mg/kg, initiated at ~26 weeks	Fur density restored (infrared imaging); running activity increased from 1.37 km/day toward wildtype 9.37 km/day; plasma urea normalized	[1]
Baar et al. (2017) Cell	Naturally aged C57BL/6J (p16::3MR), 104–130 wks; 5 mg/kg i.p., 3 doses over 5 days; observed 30 days	Reduced plasma urea and creatinine (restored renal function); reduced p16-driven bioluminescence; improved responsiveness to stimuli	[1]
Zhang et al. (2020) Aging	Naturally aged male C57BL/6 (20–24 mo); 5 mg/kg i.p., 3 doses every other day; analyzed 30 days post-treatment	Serum testosterone significantly increased (p<0.05); decreased p53, p21, p16 in testes; reduced IL-1β, IL-6, TGF-β; no change in body/testis weight	[4]
Hu et al. (2026) Front. Bioeng. Biotech.	Naturally aged mice (17 mo); 5 mg/kg i.p., every 2 days for 1 month	Aortic wall significantly thinner (p<0.05); lower PWV (improved elasticity); downregulated P21/P16; upregulated Ki-67/Lamin B; decreased IL-1β, IL-6, CXCL15, TNF-α	[5]
Hu et al. (2026) Front. Bioeng. Biotech.	D-galactose progeroid mice (200 mg/kg/day D-gal for 8 wks); 5 mg/kg i.p., every 2 days for 4 weeks	Reduced aortic wall thickness; reduced ROS (DHE staining); improved blood flow; confirmed p53/Bcl-2/Caspase-3 pathway activation	[5]
Han et al. (2022) J. Cell. Mol. Med.	Bleomycin-induced pulmonary fibrosis mouse model	Decreased senescent cells; attenuated BLM-induced collagen deposition; increased AEC2 percentage; decreased myofibroblasts	[8]
Toxicity Data Cleara/Patent	C57BL/6J mice; MTD 2x/week for 4 weeks; acute toxicity up to 100 mg/kg single dose (BALB/c)	At 5 mg/kg: well tolerated, no obvious side effects. At MTD: decreased body weight, elevated platelet counts, elevated ALP/ALT/AST. Acute 100 mg/kg: no mortality or observable toxicity within 24h	[1]

In Vitro / Human Cell Studies

Study	Cell Type	Key Results	Ref
Baar et al. (2017)	Human IMR90 fibroblasts (IR/Doxorubicin-induced senescence)	Potent, selective reduction in senescent cell viability; 11.73-fold selectivity vs non-senescent cells; p53 mitochondrial translocation; caspase-3/7 activation; non-senescent cells unaffected	[1]
Huang et al. (2021)	Human chondrocytes (PDL9 senescent vs PDL3 non-senescent)	25 µM for 5 days: removed >50% senescent cells; SA-β-gal <5% remaining; decreased p16, p21, p53; reduced IL-6, IL-8 SASP; non-senescent PDL3 cells unaffected	[6]
Zhang et al. (2020)	Human testicular tissue (observational immunofluorescence)	FOXO4 localized to Leydig cell nuclei in elderly men (≥65 yrs) but cytoplasmic in young men (<30 yrs); validates FOXO4 as a human aging target; correlated with reduced steroidogenic enzyme expression	[4]
Bourgeois et al. (2025)	Solution NMR structural analysis (p53-FOXO4-DRI complex)	Identified p53 TAD2 as specific binding site; both peptide and p53 TAD2 fold synergistically upon binding; phospho-Ser46/Thr55 enhances affinity; HIV-TAT contributes stabilizing contacts	[2]

Clinical / Human Trial Status

There are currently no completed or published human clinical trials for FOXO4-DRI. The compound remains in the preclinical stage. Cleara Biotech describes itself as a "preclinical-stage company" and is preparing the lead candidate CL04183 for Investigational New Drug (IND) applications. Some private wellness clinics offer FOXO4-DRI off-label; these are not registered clinical trials and the substance is not FDA-approved for human use.[1]

Dosage Summary

Setting	Dose	Route / Schedule	Notes
In Vitro (standard)	25 µM	Cell culture; 5 days exposure	Most common effective concentration[1][6]
In Vitro (range)	6.25–50 µM	Cell culture	Dose-dependent senolytic effect[1]
In Vivo (standard)	5 mg/kg	i.p. or i.v.; 3 doses every other day, or every 2 days for 1 month	Used across all major efficacy studies[1][4][5]
Acute Toxicity	Up to 100 mg/kg	Single i.v. injection (BALB/c mice)	No mortality or observable toxicity within 24h
Human (clinical)	None established	No clinical trials conducted	Off-label clinics report 100–400 mcg/kg (not validated)

Safety Profile

Parameter	At Therapeutic Dose (5 mg/kg)	At High Dose (MTD)
Body Weight	No significant change	Decreased total body weight
Platelet Counts	No thrombocytopenia (unlike BCL-2 inhibitors)	Elevated platelet counts
Liver Enzymes	Normal ALT, AST levels	Elevated ALP, ALT, AST (liver toxicity)
Kidney Function	Normal BUN, creatinine	Not separately reported
Long-term Tolerability	Over 10 months, 3x/week: no obvious side effects	Narrower therapeutic window[1]
In Vitro (human cells)	Non-senescent fibroblasts and chondrocytes consistently unaffected at senolytic doses[1][6]