Back to discover

Protein / target

Forkhead box protein O3

Encoded byFOXO3O43524Homo sapiensSwiss-Prot
Small-molecule tractable
Druggability
Structure with Ligand
1
Research papers

Protein at a glance

Biological role

Sequence-specific double-stranded DNA binding

Strongest disease association

Intelligence

Via encoding gene FOXO3 · Genetic evidence · score 0.83

Research activity

Emerging research

1 papers · latest 2019

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy.

View complete UniProt function annotation

Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302)

Subcellular location

Cytoplasm, cytosolNucleusMitochondrion matrixMitochondrion outer membrane
Domains and Gene Ontology detail (54)

Gene Ontology

  • Cchromatin
  • Ccytoplasm
  • Ccytosol
  • Cmitochondrial matrix
  • Cmitochondrial outer membrane
  • Cnucleoplasm
  • Cnucleus
  • Cprotein-containing complex
  • Fbeta-catenin binding
  • Fchromatin DNA binding
  • FDNA binding
  • FDNA-binding transcription activator activity, RNA polymerase II-specific

673 aa · 71 kDa · 2 isoforms

Biological roles

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Lipid & lipoprotein metabolismUniProt · GOCell migrationGOTranscriptional regulationUniProt · GOApoptosis & cell deathGO
View supporting evidence

Lipid & lipoprotein metabolism

  • ·Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A…
  • ·response to fatty acid

Cell migration

  • ·negative regulation of cell migration

Transcriptional regulation

  • ·Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A…
  • ·DNA-binding transcription activator activity, RNA polymerase II-specific
  • ·DNA-binding transcription factor activity
  • ·DNA-binding transcription factor activity, RNA polymerase II-specific

Apoptosis & cell death

  • ·apoptotic process
  • ·positive regulation of apoptotic process
  • ·positive regulation of endothelial cell apoptotic process
  • ·positive regulation of hydrogen peroxide-mediated programmed cell death

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene FOXO3

Gene-level evidence surfaced through the gene FOXO3that encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Intelligence
0.83Well supported

Genetic evidence dominant · Open Targets 0.51

Schizophrenia
0.69Moderately supported

Genetic evidence dominant · Open Targets 0.42

Smoking initiation
0.63Moderately supported

Genetic evidence dominant · Open Targets 0.38

Alzheimer's Disease
0.44Preliminary

Pathway evidence dominant · Open Targets 0.57 · no direct causal or clinical evidence

Carcinoma, Ductal, Breast
0.41Limited support

Somatic mutation evidence dominant · Open Targets 0.38

View evidence synthesis (5)
IntelligenceWell supported
0.83
agreement 0.710.95
Genetic100%

Open Targets aggregate 0.51 · 1 independent evidence family

SchizophreniaModerately supported
0.69
agreement 0.550.82
Genetic99%Literature1%

Open Targets aggregate 0.42 · 2 independent evidence families

Smoking initiationModerately supported
0.63
agreement 0.510.75
Genetic100%

Open Targets aggregate 0.38 · 1 independent evidence family

Alzheimer's DiseasePreliminary
0.44
agreement 0.260.61
Pathway76%Literature24%

Open Targets aggregate 0.57 · 2 independent evidence families · no direct causal or clinical evidence

Carcinoma, Ductal, BreastLimited support
0.41
agreement 0.250.57
Somatic mutation93%Literature7%

Open Targets aggregate 0.38 · 2 independent evidence families

This ranking differs from Open Targets' own: re-weighting moves genetically-evidenced diseases above more heavily co-mentioned ones. The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations
Alzheimer's Disease0.57
Intelligence0.51
Neurodegenerative Diseases0.46
Schizophrenia0.42
Smoking initiation0.38
Carcinoma, Ductal, Breast0.38
Prostate adenocarcinoma0.37
Lymphoid neoplasm0.37

Tractability

Small moleculesEmerging

Feasibility evidence (structure with ligand) — no clinical-stage drug of this modality recorded.

AntibodiesEmerging

Feasibility evidence (uniprot loc high conf) — no clinical-stage drug of this modality recorded.

Protein degradersEmerging

Feasibility evidence (uniprot ubiquitination and database ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (4)
SM · Structure with LigandAB · UniProt loc high confPR · UniProt UbiquitinationPR · Database Ubiquitination

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

regulation of transcription factor activityToxCast

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Research activity

1 papers · to 2019

Papers linked directly to this protein. This is the protein's own literature — descriptor-derived papers are kept separate below.

Most cited

Recent

Europe PMC papers linked directly to this protein.