FOXO4-DRI

Alameen AAM, Al-Kuraishy HM, Fawzy MN, Batiha GE

Naunyn-Schmiedeberg's archives of pharmacology

Review synthesizing preclinical evidence on the FOXO4-p53 senescence axis in brain aging research; reports that FOXO4-DRI administration in aged mammalian and neurodegeneration rodent models reduced senescent-cell accumulation, restored cerebral blood flow and blood-brain-barrier integrity measures, and improved hippocampal structure and cognitive-performance readouts in models of aging, Alzheimer's disease, and tauopathy.

Hu Z, Li F, Hu C, Shan Q, Tang Z, Jiang M, et al.

Frontiers in bioengineering and biotechnology

In naturally aged and progeroid mouse models plus oxygen-glucose-deprivation-induced senescent endothelial cell cultures, researchers found FOXO4-DRI disrupted FOXO4-p53 binding, promoted nuclear exclusion of phosphorylated p53, and activated the p53/BCL-2/Caspase-3 pathway to drive apoptosis selectively in senescent endothelial cells, improving aortic vascular-function measures in aged mice.

Kong YX, Li ZS, Liu YB, Pan B, Fu X, Xiao R, et al.

Communications biology

Using human keloid organ cultures and fibroblast cell models, researchers identified elevated p53-serine15 phosphorylation and senescence markers (p16, SASP genes) in keloid tissue, and found FOXO4-DRI promoted apoptosis and nuclear exclusion of phosphorylated p53 in senescent keloid fibroblasts, reducing G0/G1-arrested cell populations in culture.

Meng J, Li Y, Wan C, Sun Y, Dai X, Huang J, et al.

JCI insight

In non-small cell lung cancer cell models and mice, radiation exposure induced a senescence-like phenotype in cancer-associated fibroblasts that promoted tumor cell proliferation via the JAK/STAT pathway; FOXO4-DRI selectively induced apoptosis in these senescence-like fibroblasts, radiosensitizing lung cancer cells in vitro and in vivo, and reduced markers of radiation-induced pulmonary fibrosis in mouse lungs.

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, et al.

Cell

Foundational study identifying FOXO4 as a regulator of senescent-cell viability; researchers designed a FOXO4 peptide disrupting the FOXO4-p53 interaction, causing p53 nuclear exclusion and cell-intrinsic apoptosis selectively in senescent cells in culture, and found that peptide administration in fast-aging (Xpd) and naturally aged mouse models restored fitness, fur density, and kidney-function measures and mitigated doxorubicin-induced chemotoxicity in mice.