HMGB1 — High Mobility Group Box 1

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HMGB1 — High Mobility Group Box 1

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HMGB1 — High Mobility Group Box 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HMGB1 — High Mobility Group Box 1</th>
</tr>
<tr> [@santoro2016]
<td class="label">Symbol</td> [@yang2015]
<td><strong>HMGB1</strong></td> [@venereau2012]
</tr> [@magna2014]
<tr>
<td class="label">Full Name</td>
<td>High Mobility Group Box 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>13q12.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3146" target="_blank">3146</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000189403" target="_blank">ENSG00000189403</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/163905" target="_blank">163905</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P09429" target="_blank">P09429</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), Stroke, Traumatic Brain Injury</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous; enriched in [neurons](/entities/neurons), microglia, [astrocytes](/entities/astrocytes)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Features</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">DAMP (danger signal)<br>[TLR4](/en

...

HMGB1 — High Mobility Group Box 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">HMGB1 — High Mobility Group Box 1</th>
</tr>
<tr> [@santoro2016]
<td class="label">Symbol</td> [@yang2015]
<td><strong>HMGB1</strong></td> [@venereau2012]
</tr> [@magna2014]
<tr>
<td class="label">Full Name</td>
<td>High Mobility Group Box 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>13q12.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3146" target="_blank">3146</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000189403" target="_blank">ENSG00000189403</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/163905" target="_blank">163905</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P09429" target="_blank">P09429</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), Stroke, Traumatic Brain Injury</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous; enriched in [neurons](/entities/neurons), microglia, [astrocytes](/entities/astrocytes)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Features</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">DAMP (danger signal)<br>[TLR4](/entities/tlr4)/RAGE ligand<br>Nuclear DNA-binding protein<br>Redox-sensitive alarmin</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">604 edges</a></td>
</tr>
</table>

HMGB1 — High Mobility Group Box 1

Pathway Diagram

Mermaid diagram (expand to render)

Overview

HMGB1 (High Mobility Group Box 1) is a gene on chromosome 13q12.3 encoding a highly conserved, ubiquitously expressed nuclear protein that functions both as a chromatin architectural factor and as an extracellular danger-associated molecular pattern (DAMP). In the nucleus, HMGB1 bends DNA and facilitates transcription factor binding. When released from damaged or dying neurons, HMGB1 acts as a potent alarmin that activates [microglia](/cell-types/microglia-neuroinflammation) and astrocytes through [TLR4](/genes/tlr4) and [RAGE](/genes/rage) receptors, driving neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [ALS](/diseases/als), and acute brain injuries.

> Key takeaway: HMGB1 is a dual-function protein — chromatin regulator inside the nucleus, potent inflammatory mediator when released extracellularly. Its role as a DAMP makes it a central amplifier of neuroinflammation across neurodegenerative diseases.

Gene Structure and Expression

Genomic Organization

HMGB1 spans approximately 7.5 kb on chromosome 13q12.3, comprising 5 exons. The gene is one of four HMGB family members (HMGB1-4), with HMGB1 being the most abundant and broadly expressed. The gene encodes a 215-amino acid protein with two DNA-binding HMG box domains (A-box and B-box) and an acidic C-terminal tail.

Brain Expression Pattern

HMGB1 is expressed ubiquitously but shows enrichment in:

Neurons: High nuclear expression in cortical, hippocampal, and cerebellar neurons
[Microglia](/cell-types/microglia-neuroinflammation): Expression increases dramatically upon activation; microglia are the primary source of extracellular HMGB1 in the CNS
[Astrocytes](/cell-types/astrocytes): Moderate expression, with active secretion during reactive astrogliosis
[Oligodendrocytes](/cell-types/oligodendrocytes): Low basal expression

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=HMGB1).

Transcriptional Regulation

HMGB1 expression is regulated by:

[NF-κB](/genes/nfkb1): Inflammatory activation increases HMGB1 transcription
[p53](/entities/tp53): DNA damage response upregulates HMGB1
Interferon regulatory factors: [IRF1](/genes/irf1) and [IRF3](/genes/irf3) regulate HMGB1 in innate immune responses
Epigenetic control: Promoter methylation and histone acetylation modulate tissue-specific expression levels

Function

Nuclear Functions

Inside the nucleus, HMGB1 functions as a chromatin architectural protein:

DNA bending: HMGB1 binds the minor groove of DNA and induces sharp bends, facilitating nucleosome remodeling and transcription factor access
Transcription regulation: Enhances binding of [p53](/entities/tp53), steroid hormone receptors, and [NF-κB](/genes/nfkb1) to their target sequences
DNA repair: HMGB1 participates in base excision repair, nucleotide excision repair, and mismatch repair by facilitating access of repair enzymes
V(D)J recombination: Required for proper immunoglobulin gene rearrangement
Telomere maintenance: HMGB1 associates with telomeric DNA and regulates telomere length

Extracellular Functions (DAMP Activity)

When released extracellularly — passively from necrotic cells or actively secreted by activated immune cells — HMGB1 becomes a potent inflammatory mediator:

[RAGE](/genes/rage) signaling: HMGB1 binds the Receptor for Advanced Glycation End Products, activating [NF-κB](/genes/nfkb1), [MAPK](/genes/mapk1) cascades, and pro-inflammatory gene expression

[TLR4](/genes/tlr4) activation: Disulfide-HMGB1 signals through TLR4/[MD-2](/proteins/md2-protein) complex, activating [MyD88](/genes/myd88)-dependent and TRIF-dependent pathways

[TLR2](/genes/tlr2) engagement: HMGB1-nucleosome complexes activate TLR2 signaling

CXCL12 partnership: HMGB1 forms a heterocomplex with the chemokine CXCL12 that signals through CXCR4 to recruit immune cells

[NLRP3](/genes/nlrp3) inflammasome activation: Extracellular HMGB1 primes and activates the [NLRP3 inflammasome](/entities/nlrp3-inflammasome), leading to [IL-1β](/genes/il1b) and IL-18 release

Redox-Dependent Signaling

HMGB1 activity is critically regulated by its redox state:

All-thiol HMGB1 (C23, C45, C106 all reduced): Chemoattractant, promotes cell migration via CXCR4
Disulfide HMGB1 (C23-C45 disulfide bond, C106 reduced): Pro-inflammatory cytokine inducer via TLR4
Sulfonyl HMGB1 (C106 oxidized to sulfonic acid): Immunologically inactive, promotes resolution of inflammation

This redox switch makes HMGB1 a sensor of the tissue oxidative environment, directly coupling [oxidative stress](/mechanisms/oxidative-stress) to inflammation.

Disease Associations

Alzheimer's Disease

HMGB1 plays multiple roles in [AD](/diseases/alzheimers-disease) pathogenesis:

Amyloid amplification: Extracellular HMGB1 binds [amyloid-β](/proteins/amyloid-beta-protein) oligomers and fibrils, forming HMGB1-[Aβ](/proteins/amyloid-beta) complexes that activate microglia more potently than Aβ alone
Neuroinflammation: HMGB1 released from degenerating neurons activates microglial [TLR4](/genes/tlr4) and [RAGE](/genes/rage), sustaining chronic inflammation around [amyloid plaques](/mechanisms/amyloid-pathology)
[Tau](/proteins/tau) pathology: HMGB1 promotes [tau](/proteins/tau) phosphorylation through [RAGE](/entities/rage-receptor)-mediated [GSK3β](/genes/gsk3b) activation
[Blood-brain barrier](/entities/blood-brain-barrier) disruption: HMGB1 increases BBB permeability through endothelial RAGE signaling
CSF biomarker: Elevated HMGB1 levels in CSF correlate with disease severity and inflammatory markers

Postmortem studies show increased HMGB1 cytoplasmic translocation and extracellular release in AD [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex) compared to age-matched controls.

Parkinson's Disease

In [PD](/diseases/parkinsons-disease):

HMGB1 is released from degenerating dopaminergic neurons in the [substantia nigra](/brain-regions/substantia-nigra)
Activates microglial [TLR4](/genes/tlr4) signaling, sustaining dopaminergic neurotoxicity
[α-Synuclein](/proteins/alpha-synuclein) aggregates trigger HMGB1 release from neurons
Anti-HMGB1 antibodies are neuroprotective in MPTP and 6-OHDA PD models
HMGB1 levels are elevated in PD patient serum and CSF

ALS

In [amyotrophic lateral sclerosis](/diseases/als):

HMGB1 is released from degenerating motor neurons
Activates spinal cord microglia and astrocytes through [TLR4](/genes/tlr4) and RAGE
Plasma HMGB1 levels correlate with disease progression rate
[TDP-43](/proteins/tdp-43-protein) aggregation promotes HMGB1 nuclear-to-cytoplasmic translocation

Stroke and Traumatic Brain Injury

Massive HMGB1 release occurs within hours of ischemic injury
HMGB1 is one of the earliest DAMPs released after neuronal death
Anti-HMGB1 strategies reduce infarct volume in preclinical stroke models

Expression

Developmental and Aging Patterns

| Context | HMGB1 Level | Significance |
|---|---|---|
| Embryonic brain | Very high (nuclear) | Chromatin remodeling, neurogenesis |
| Adult brain | Moderate (nuclear) | Transcription regulation |
| Aging brain | Increased cytoplasmic | Cellular stress, senescence |
| AD brain | High extracellular | Neuroinflammation amplification |
| Post-injury | Massive release | DAMP signaling, sterile inflammation |

Regulation During Neurodegeneration

HMGB1 undergoes a characteristic nuclear-to-cytoplasmic translocation during neurodegeneration:

Nuclear HMGB1 is hyperacetylated by stress-activated acetyltransferases

Acetylation exposes nuclear export signals, driving cytoplasmic accumulation

Cytoplasmic HMGB1 is actively secreted via lysosomal exocytosis or passively released during necrosis

Extracellular HMGB1 amplifies inflammation through paracrine and autocrine loops

Therapeutic Targeting

Anti-HMGB1 Strategies

Anti-HMGB1 monoclonal antibodies: Neutralizing antibodies reduce neuroinflammation in AD, PD, and stroke models
BoxA (HMGB1 antagonist): The A-box domain of HMGB1 acts as a competitive antagonist, blocking HMGB1-receptor interactions
Glycyrrhizin: Natural compound from licorice root that directly binds HMGB1 and inhibits its extracellular activity; neuroprotective in multiple preclinical models
Ethyl pyruvate: Inhibits HMGB1 secretion by activated macrophages/microglia
RAGE inhibitors: FPS-ZM1 and other small molecule RAGE antagonists block HMGB1-RAGE signaling
[TLR4](/genes/tlr4) antagonists: TAK-242 (resatorvid) blocks HMGB1-TLR4 signaling

Clinical Considerations

HMGB1 is a validated therapeutic target in multiple inflammatory conditions
The redox-dependent activity provides opportunities for selective targeting
Combination with anti-amyloid or anti-tau therapies may address both pathology triggers and inflammatory amplification

External Links

[HMGB1 at NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/3146)
[HMGB1 at UniProt (P09429)](https://www.uniprot.org/uniprot/P09429)
[HMGB1 at OMIM (163905)](https://omim.org/entry/163905)
[HMGB1 at GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=HMGB1)
[Allen Brain Atlas — HMGB1](https://human.brain-map.org/microarray/search/show?search_term=HMGB1)

References

[Scaffidi et al., Release of chromatin protein HMGB1 by necrotic cells triggers inflammation (2002) (2002)](https://doi.org/10.1038/nature01023)

[Yang et al., HMGB1 as a cytokine and therapeutic target (2005) (2005)](https://doi.org/10.1189/jlb.1104648)

[Paudel et al., HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction (2018) (2018)](https://doi.org/10.3389/fnins.2018.00628)

[Fujita et al., HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease (2016) (2016)](https://doi.org/10.1038/srep31895)

[Santoro et al., In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease (2016) (2016)](https://doi.org/10.1016/j.nbd.2015.12.004)

[Yang et al., MD-2 is required for disulfide HMGB1-dependent TLR4 signaling (2015) (2015)](https://doi.org/10.1084/jem.20141318)

[Venereau et al., Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release (2012) (2012)](https://doi.org/10.1084/jem.20120189)

[Unknown, Magna & Bhagavathula, The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases (2014) (2014)](https://doi.org/10.1007/s12016-013-8373-0)

Pathway Diagram

The following diagram shows the key molecular relationships involving HMGB1 — High Mobility Group Box 1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

HMGB1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-hmgb1
kg_node_id	HMGB1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-0a636dd9a23e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-hmgb1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

35

Outgoing

46

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HMGB1 — High Mobility Group Box 1

HMGB1 — High Mobility Group Box 1

HMGB1 — High Mobility Group Box 1

HMGB1 — High Mobility Group Box 1

Pathway Diagram

Overview

Gene Structure and Expression

Genomic Organization

Brain Expression Pattern

Transcriptional Regulation

Function

Nuclear Functions

Extracellular Functions (DAMP Activity)

Redox-Dependent Signaling

Disease Associations

Alzheimer's Disease

Parkinson's Disease

ALS

Stroke and Traumatic Brain Injury

Expression

Developmental and Aging Patterns

Regulation During Neurodegeneration

Therapeutic Targeting

Anti-HMGB1 Strategies

Clinical Considerations

See Also

External Links

References

Pathway Diagram

💬 Discussion