Enterprise AI Analysis
Decoding HMGB1: A Redox-Sensitive DAMP
Unveiling the multifaceted roles of HMGB1 in inflammation, cell death, and immune regulation through its redox isoforms.
Man Sup Kwak et al. • Published online: 13 February 2026
Executive Impact: Key Insights for Enterprise
HMGB1, a pivotal DAMP, has broad implications from cellular stress response to chronic inflammatory diseases. Understanding its redox-dependent functions offers novel therapeutic avenues.
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Cysteine Residues Dictate Function
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Redox Isoforms Drive Diverse Roles
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Years of Research Impact
Deep Analysis & Enterprise Applications
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Introduction: HMGB1 as a Critical DAMP
Damage-associated molecular patterns (DAMPs) are endogenous danger signals generated in response to pathogen invasion, cellular damage or oxidative stress. HMGB1 is a key DAMP, playing crucial roles in both septic and sterile inflammation by interacting with various pattern recognition receptors (PRRs) like TLRs and RAGE, leading to inflammatory cytokine production and immune cell recruitment. Understanding DAMPs, including HMGB1, is vital for developing therapeutic strategies against inflammatory and autoimmune diseases.
HMGB1 Structure and Post-Translational Modifications
HMGB1 consists of two HMG-box domains (A and B) and an acidic C-terminal tail, containing three critical cysteine residues (C23, C45, C106). These residues are key to HMGB1's redox sensitivity, allowing it to exist in reduced (Re-HMGB1), disulfide (Ds-HMGB1), oxidized (Ox-HMGB1), and dimerized (Di-HMGB1) isoforms. Post-translational modifications (PTMs) such as oxidation, lactylation, nitrosylation, phosphorylation, acetylation, glycosylation, methylation, and ubiquitination tightly regulate its DNA-binding, subcellular localization, and secretion mechanisms.
Intracellular Roles of HMGB1 Redox Isoforms
In the nucleus, HMGB1 acts as a DNA chaperone, regulating chromatin structure and preventing DNA damage. Under oxidative stress, Re-HMGB1 forms Ds-HMGB1 (C23-C45 disulfide bond), while excessive ROS can lead to Di-HMGB1 (C106-C106 intermolecular disulfide bond) which strongly binds DNA, protecting against damage. Cytoplasmic HMGB1 is crucial for mitochondrial homeostasis, autophagy initiation (by binding Beclin-1), and inhibiting protein aggregation (chaperone-like activity). It also modulates cancer cell senescence via the STING pathway and influences JAK2-STAT3 signaling for PD-L1 expression.
Extracellular Roles of HMGB1 Redox Isoforms
Extracellular HMGB1 acts as a DAMP, interacting with various receptors to promote inflammation. Ds-HMGB1 and Di-HMGB1 (intermolecular C106-C106 disulfide bond) enhance proinflammatory signaling by activating TLR2, TLR4, TLR9 and RAGE, leading to increased cytokine release and NF-κB activation. Re-HMGB1 acts as a chemoattractant (via CXCR4) and can also promote autophagy (via RAGE). HMGB1 can form complexes with PAMPs (LPS, LTA) and nucleic acids (DNA, RNA), amplifying immune responses through TLRs and cytosolic sensors (RIG-I, MDA5, AIM2). Its redox state determines if it's immune-activating or immunologically silent (Ox-HMGB1).
HMGB1 and Regulated Cell Death Pathways
HMGB1 is released passively during various forms of cell death, with its redox state influencing subsequent cellular fate. During necrosis, early release is reduced HMGB1, later becoming oxidized. Necroptosis, pyroptosis (driven by inflammasome-activated caspase-1), and ferroptosis (iron-dependent cell death) all involve HMGB1 release, often in its Ds-HMGB1 form. Apoptosis typically sequesters HMGB1, and if released, it's hyperoxidized (inactive). HMGB1 can also actively induce cell death; for instance, extracellular HMGB1 can amplify necrosis via TLR4-TRIF-RIPK3, activate ferroptosis via TLR4-CXCR4, or promote apoptosis via RAGE interactions, depending on context.
HMGB1 Redox States in Immune Disorders
HMGB1 redox isoforms are implicated in various inflammatory and autoimmune diseases. Ds-HMGB1 is linked to BBB dysfunction, microglia activation in CNS injuries, fibrosis in liver, severe inflammation in pancreatitis, and myositis. Elevated Ds-HMGB1 in portal blood correlates with IRI severity in liver transplantation. In autoimmune conditions like rheumatoid arthritis, systemic sclerosis, and juvenile idiopathic arthritis, Ds-HMGB1 promotes inflammation. In cancer, Ds-HMGB1 is predominant in the TME and promotes tumor growth. Oxidative stress can promote Di-HMGB1 formation, further exacerbating chronic inflammation across various tissues.
Critical Residues for HMGB1 Function
C23, C45, C106Key Cysteine Residues in HMGB1 Redox Sensitivity
The functional diversity of HMGB1 hinges on the redox state of these three cysteine residues, dictating its role in DNA repair, inflammation, and cell death pathways.
Enterprise Process Flow
Reduced HMGB1 (Re-HMGB1)
→
Mild Oxidative Stress (PrxI/II)
→
Disulfide HMGB1 (Ds-HMGB1, C23-C45 bond)
→
Inflammatory Signaling (TLR4/RAGE)
→
Excessive Oxidative Stress (ROS)
→
Oxidized HMGB1 (Ox-HMGB1, -SO3H on Cys)
→
Immune Tolerance
→
Intermolecular Dimerization (Di-HMGB1, C106-C106 bond)
→
Enhanced Proinflammatory Response
| Redox Isoform | Intracellular Role | Extracellular Role |
|---|---|---|
| Re-HMGB1 | DNA chaperone, Autophagy (Beclin-1 binding), Mitochondrial homeostasis |
|
| Ds-HMGB1 | DNA binding (C23-C45 bond), Stabilizes chromatin |
|
| Ox-HMGB1 | Loss of DNA binding | Immunologically inert, Immune tolerance (apoptotic contexts) |
| Di-HMGB1 | Enhanced DNA binding, Protects against DNA damage, Potentiates JAK2-STAT3 signaling | Enhanced pro-inflammatory DAMP (TLR2, TLR4) |
Clinical Implications of HMGB1 Redox States in Sepsis
In patients with septic shock, high circulating HMGB1 levels correlate with disease severity and mortality. Early in sepsis, HMGB1 is often in its reduced form, but as the condition progresses and oxidative stress increases, HMGB1 undergoes oxidation and dimerization. The presence of Ds-HMGB1 and Di-HMGB1 is directly linked to amplified inflammatory responses, mitochondrial dysfunction, and increased cytokine release. Therapeutic strategies targeting specific redox forms of HMGB1, such as neutralizing antibodies against Ds-HMGB1 or inhibiting its oxidation, have shown promise in experimental models by improving clinical outcomes and reducing systemic inflammation. This highlights HMGB1's potential as a diagnostic marker and a therapeutic target in critical inflammatory conditions.
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