Pathway Human Homo sapiens

FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes

R-HSA-9615017 in Reactome release 97: under FOXO-mediated transcription, with 30 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9615017 (mouse), R-RNO-9615017 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9615017.2
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2018-12-13
Events inside: 34, counted from the record

FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016).

FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).

FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.

In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.

FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.

FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).

Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).

Literature Reactome attaches

FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical developmentProc. Natl. Acad. Sci. U.S.A., 2016PubMed 27791111
Direct control of the Forkhead transcription factor AFX by protein kinase BNature, 1999, vol. 398, p. 630-4PubMed 10217147
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stressNature, 2002, vol. 419, p. 316-21PubMed 12239572
Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stressPLoS ONE, 2013, vol. 8, p. e73875PubMed 24040102
FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3Hum. Mol. Genet., 2011, vol. 20, p. 2928-41PubMed 21536589
CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress PathwayOxid Med Cell Longev, 2016, vol. 2016, p. 7410257PubMed 27547294
AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle

Reactome's record lists 8 orthologous events, R-RNO-9615017 (Rattus norvegicus), R-MMU-9615017 (Mus musculus) among the species this site serves, and 6 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9615017 with StableID: R-HSA-9615017.2 (accessed 2026-10-01 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 30 genes in this human pathway; showing 1 to 30, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneABCA6	AuthorityHGNC:36	Mapping file id23460 NCBI file	EvidenceTAS
GeneAGRP	AuthorityHGNC:330	Mapping file id181 NCBI file	EvidenceIEA
GeneATXN3	AuthorityHGNC:7106	Mapping file id4287 NCBI file	EvidenceTAS
GeneCAT	AuthorityHGNC:1516	Mapping file id847 NCBI file	EvidenceIEA
GeneFBXO32	AuthorityHGNC:16731	Mapping file id114907 NCBI file	EvidenceIEA
GeneFOXO1	AuthorityHGNC:3819	Mapping file id2308 NCBI file	EvidenceIEA, TAS
GeneFOXO3	AuthorityHGNC:3821	Mapping file id2309 NCBI file	EvidenceIEA, TAS
GeneFOXO4	AuthorityHGNC:7139	Mapping file id4303 NCBI file	EvidenceIEA, TAS
GeneFOXO6	AuthorityHGNC:24814	Mapping file idENSG00000204060 Ensembl file	EvidenceIEA
GeneG6PC1	AuthorityHGNC:4056	Mapping file id2538 NCBI file	EvidenceIEA
GeneGCK	AuthorityHGNC:4195	Mapping file id2645 NCBI file	EvidenceIEA
GeneHDAC1	AuthorityHGNC:4852	Mapping file id3065 NCBI file	EvidenceIEA
GeneHDAC2	AuthorityHGNC:4853	Mapping file id3066 NCBI file	EvidenceIEA
GeneIGFBP1	AuthorityHGNC:5469	Mapping file id3484 NCBI file	EvidenceTAS
GeneINS	AuthorityHGNC:6081	Mapping file id3630 NCBI file	EvidenceIEA, TAS
GeneNPY	AuthorityHGNC:7955	Mapping file id4852 NCBI file	EvidenceTAS
GeneNR3C1	AuthorityHGNC:7978	Mapping file id2908 NCBI file	EvidenceIEA
GenePCK1	AuthorityHGNC:8724	Mapping file id5105 NCBI file	EvidenceIEA
GenePLXNA4	AuthorityHGNC:9102	Mapping file id91584 NCBI file	EvidenceIEA
GenePOMC	AuthorityHGNC:9201	Mapping file id5443 NCBI file	EvidenceIEA
GenePPARGC1A	AuthorityHGNC:9237	Mapping file id10891 NCBI file	EvidenceIEA
GeneRETN	AuthorityHGNC:20389	Mapping file id56729 NCBI file	EvidenceIEA
GeneSIN3A	AuthorityHGNC:19353	Mapping file id25942 NCBI file	EvidenceIEA
GeneSIRT3	AuthorityHGNC:14931	Mapping file id23410 NCBI file	EvidenceIEA, TAS
GeneSMAD2	AuthorityHGNC:6768	Mapping file id4087 NCBI file	EvidenceIEA
GeneSMAD3	AuthorityHGNC:6769	Mapping file id4088 NCBI file	EvidenceIEA
GeneSMAD4	AuthorityHGNC:6770	Mapping file id4089 NCBI file	EvidenceIEA
GeneSOD2	AuthorityHGNC:11180	Mapping file id6648 NCBI file	EvidenceTAS
GeneSREBF1	AuthorityHGNC:11289	Mapping file id6720 NCBI file	EvidenceIEA
GeneTRIM63	AuthorityHGNC:16007	Mapping file id84676 NCBI file	EvidenceIEA

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

FOXO-mediated transcriptionR-HSA-961408566 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.