Pathway Human Homo sapiens

Cytoprotection by HMOX1

R-HSA-9707564 in Reactome release 97: under Cellular response to chemical stress, with 60 genes placed in it by the mapping files and 1 child pathway 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-9707564 (mouse), R-RNO-9707564 (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-9707564.6
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2021-03-23
Last updated: 2022-04-07
Events inside: 19, counted from the record

Expression of heme oxygenase 1 (HMOX1) is regulated by various indicators of cell stress, while HMOX2 is expressed constitutively. Both catalyze the breakdown of heme into biliverdin (BV), carbon monoxide (CO), and ferrous iron. Biliverdin is immediately reduced to bilirubin (BIL). Both bilirubin and carbon monoxide can localize to different compartments and outside the cell. Cytoprotection by HMOX1 is exerted directly by HMOX1 and by the antioxidant metabolites produced through the degradation of heme. Additionally, due to the reactive nature of labile heme, its degradation is intrinsically protective.

HMOX1 confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and immune cell proliferation. It binds to the NACHT domain of NLRP3 inflammasome, blocking its activation. In mouse it directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation. It also blocks phosphorylation of STAT3 by PTK6 and co-inhibits Socs3, a negative feedback factor of Stat3 activation, as well as RORγt, thereby decreasing Th2 and Th17 immune responses, and alleviating airway inflammation.

The beneficial effects of the three products generated by HMOX1 differ not only in their inherent molecular mechanisms, but also in their downstream cellular targets. To date, this is the only enzymatic system known to exhibit such characteristics. Iron is a vital component of many biological systems and is capable of producing hydroxyl radicals via fenton chemistry. For this reason, iron is sequestered by the storage multimer ferritin and to prevent oxidative damage while maintaining the iron pool. On the other hand, the protective effects of bilirubin and CO are broadly recognized, which has led to their consideration as therapeutics for a range of diseases. Bilirubin has been recognized as one of the most potent antioxidants in nature, and moderate increases of its serum level have been shown in numerous large-scale population and epidemiological studies to have a protective effect against cardiovascular and metabolic disease. These effects are mediated by bilirubin scavenging of superoxide anions and reactive nitrogen species (RNS), and by activating the transcription factor PPAR-alpha.

CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. CO possesses intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. Binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics. The most important of these is the mitochondrial cytochrome c oxidase (Cco). By locally blocking mitochondrial respiration the main source of reactive oxygen species (ROS) in the cell is switched off. Additionally CO enables efficient reduction of methemoglobin (MetHb) by H2O2, thus preventing the generation of free heme in hemorrhagic diseases and malaria (Origassa and Câmara, 2013; Morse et al, 2009; Ryter et al, 2006; Cooper and Brown, 2008; Hinds and Stec, 2008).

Literature Reactome attaches

Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injuryWorld journal of hepatology, 2013, vol. 5, p. 541-549PubMed 24179613
Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and diseaseFree Radic Biol Med, 2009, vol. 47, p. 1-12PubMed 19362144
Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applicationsPhysiol Rev, 2006, vol. 86, p. 583-650PubMed 16601269
The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significanceJ Bioenerg Biomembr, 2008, vol. 40, p. 533-9PubMed 18839291
Bilirubin, a Cardiometabolic Signaling MoleculeHypertension, 2018, vol. 72, p. 788-795PubMed 30354722

Reactome's record lists 12 orthologous events, R-MMU-9707564 (Mus musculus), R-RNO-9707564 (Rattus norvegicus) among the species this site serves, and 10 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-05 ET · Reactome pathway browser"Cytoprotection by HMOX1". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9707564 with StableID: R-HSA-9707564.6 (accessed 2026-10-05 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 60 genes in this human pathway; showing 1 to 60, 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
GeneABCC1	AuthorityHGNC:51	Mapping file id4363 NCBI file	EvidenceTAS
GeneALB	AuthorityHGNC:399	Mapping file id213 NCBI file	EvidenceTAS
GeneBACH1	AuthorityHGNC:935	Mapping file id571 NCBI file	EvidenceTAS
GeneBLVRA	AuthorityHGNC:1062	Mapping file id644 NCBI file	EvidenceTAS
GeneBLVRB	AuthorityHGNC:1063	Mapping file id645 NCBI file	EvidenceTAS
GeneCARM1	AuthorityHGNC:23393	Mapping file id10498 NCBI file	EvidenceTAS
GeneCHD9	AuthorityHGNC:25701	Mapping file id80205 NCBI file	EvidenceTAS
GeneCOX4I1	AuthorityHGNC:2265	Mapping file id1327 NCBI file	EvidenceTAS
GeneCOX4I2	AuthorityHGNC:16232	Mapping file id84701 NCBI file	EvidenceTAS
GeneCOX5A	AuthorityHGNC:2267	Mapping file id9377 NCBI file	EvidenceTAS
GeneCOX5B	AuthorityHGNC:2269	Mapping file id1329 NCBI file	EvidenceTAS
GeneCOX6A1	AuthorityHGNC:2277	Mapping file id1337 NCBI file	EvidenceTAS
GeneCOX6A2	AuthorityHGNC:2279	Mapping file id1339 NCBI file	EvidenceTAS
GeneCOX6B1	AuthorityHGNC:2280	Mapping file id1340 NCBI file	EvidenceTAS
GeneCOX6B2	AuthorityHGNC:24380	Mapping file id125965 NCBI file	EvidenceTAS
GeneCOX6C	AuthorityHGNC:2285	Mapping file id1345 NCBI file	EvidenceTAS
GeneCOX7A1	AuthorityHGNC:2287	Mapping file id1346 NCBI file	EvidenceTAS
GeneCOX7A2	AuthorityHGNC:2288	Mapping file id1347 NCBI file	EvidenceTAS
GeneCOX7A2L	AuthorityHGNC:2289	Mapping file id9167 NCBI file	EvidenceTAS
GeneCOX7B	AuthorityHGNC:2291	Mapping file id1349 NCBI file	EvidenceTAS
GeneCOX7C	AuthorityHGNC:2292	Mapping file id1350 NCBI file	EvidenceTAS
GeneCOX8A	AuthorityHGNC:2294	Mapping file id1351 NCBI file	EvidenceTAS
GeneCOX8C	AuthorityHGNC:24382	Mapping file id341947 NCBI file	EvidenceTAS
GeneCOXFA4	AuthorityHGNC:7687	Mapping file id4697 NCBI file	EvidenceTAS
GeneCREBBP	AuthorityHGNC:2348	Mapping file id1387 NCBI file	EvidenceTAS
GeneCYCS	AuthorityHGNC:19986	Mapping file id54205 NCBI file	EvidenceTAS
GeneFABP1	AuthorityHGNC:3555	Mapping file id2168 NCBI file	EvidenceTAS
GeneHBA1	AuthorityHGNC:4823	Mapping file id3039 NCBI file	EvidenceTAS
GeneHBA2	AuthorityHGNC:4824	Mapping file id3040 NCBI file	EvidenceTAS
GeneHBB	AuthorityHGNC:4827	Mapping file id3043 NCBI file	EvidenceTAS
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceTAS
GeneHELZ2	AuthorityHGNC:30021	Mapping file id85441 NCBI file	EvidenceTAS
GeneHIGD1C	AuthorityHGNC:28044	Mapping file id613227 NCBI file	EvidenceTAS
GeneHM13	AuthorityHGNC:16435	Mapping file id81502 NCBI file	EvidenceTAS
GeneHMOX1	AuthorityHGNC:5013	Mapping file id3162 NCBI file	EvidenceIEA, TAS
GeneHMOX2	AuthorityHGNC:5014	Mapping file id3163 NCBI file	EvidenceTAS
GeneMAFK	AuthorityHGNC:6782	Mapping file id7975 NCBI file	EvidenceTAS
GeneMED1	AuthorityHGNC:9234	Mapping file id5469 NCBI file	EvidenceTAS
GeneMT-CO1	AuthorityHGNC:7419	Mapping file id4512 NCBI file	EvidenceTAS
GeneMT-CO2	AuthorityHGNC:7421	Mapping file id4513 NCBI file	EvidenceTAS
GeneMT-CO3	AuthorityHGNC:7422	Mapping file id4514 NCBI file	EvidenceTAS
GeneNCOA1	AuthorityHGNC:7668	Mapping file id8648 NCBI file	EvidenceTAS
GeneNCOA2	AuthorityHGNC:7669	Mapping file id10499 NCBI file	EvidenceTAS
GeneNCOA6	AuthorityHGNC:15936	Mapping file id23054 NCBI file	EvidenceTAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceTAS
GeneNCOR2	AuthorityHGNC:7673	Mapping file id9612 NCBI file	EvidenceTAS
GeneNFE2L2	AuthorityHGNC:7782	Mapping file id4780 NCBI file	EvidenceTAS
GeneNLRP3	AuthorityHGNC:16400	Mapping file id114548 NCBI file	EvidenceIEA
GenePPARA	AuthorityHGNC:9232	Mapping file id5465 NCBI file	EvidenceTAS
GenePTK6	AuthorityHGNC:9617	Mapping file id5753 NCBI file	EvidenceIEA
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceTAS
GeneSIN3A	AuthorityHGNC:19353	Mapping file id25942 NCBI file	EvidenceTAS
GeneSIN3B	AuthorityHGNC:19354	Mapping file id23309 NCBI file	EvidenceTAS
GeneSMARCD3	AuthorityHGNC:11108	Mapping file id6604 NCBI file	EvidenceTAS
GeneSTAP2	AuthorityHGNC:30430	Mapping file id55620 NCBI file	EvidenceIEA
GeneSTAT3	AuthorityHGNC:11364	Mapping file id6774 NCBI file	EvidenceIEA
GeneTBL1X	AuthorityHGNC:11585	Mapping file id6907 NCBI file	EvidenceTAS
GeneTBL1XR1	AuthorityHGNC:29529	Mapping file id79718 NCBI file	EvidenceTAS
GeneTGS1	AuthorityHGNC:17843	Mapping file id96764 NCBI file	EvidenceTAS
GeneTXNIP	AuthorityHGNC:16952	Mapping file id10628 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

Cellular response to chemical stressR-HSA-9711123199 genes

Children

Regulation of HMOX1 expression and activityR-HSA-97075875 genes

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.