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High mobility group box 1, or HMGB1, is one of the most deceptively simple proteins in human biology. Discovered in 1973 as a non-histone chromatin-binding factor, it spent decades as a quiet DNA chaperone before being unmasked as a potent alarm signal released by stressed and dying cells. Today HMGB1 sits at the center of two seemingly opposite stories: inside the nucleus it safeguards genome stability and transcription, while outside the cell it acts as a damage-associated molecular pattern that rallies the immune system and, paradoxically, promotes tissue repair. This duality — guardian of the genome and herald of inflammation — explains why HMGB1 is implicated in such a broad sweep of human disease, from sepsis and liver injury to cancer, depression, and aging itself. This review traces how a single chromatin protein acquires such pleiotropy, how its location and redox state dictate its message, and why it has become a compelling, if challenging, therapeutic target.
HMGB1 is a 215-amino-acid protein built from two homologous DNA-binding domains, the A box and the B box, followed by a long acidic C-terminal tail rich in glutamic and aspartic acid. Two nuclear localization signals govern its residence in the nucleus, where it bends DNA, facilitates nucleosome sliding, and assists in the repair of double-strand breaks. Its surface carries the precise docking sites that later determine its extracellular career: a Toll-like receptor 4 binding segment within the B box and a receptor for advanced glycation end products binding segment in the C-terminal region. What makes HMGB1 unusual is that it lacks a conventional secretion signal yet travels liberally between compartments. In homeostasis it shuttles between nucleus and cytoplasm; under cellular stress it is actively secreted by immune cells or passively released from cells undergoing necrosis. The same molecule can therefore be a quiet nuclear architect one moment and a circulating danger signal the next, depending entirely on where it sits and what post-translational marks it carries.
Figure 1. Structure of the HMGB1 protein. (Source: He SJ, et al. 2017)
The transformation of HMGB1 into an extracellular alarm begins at the moment of cell injury. Unlike apoptosis, which packages cellular contents neatly, necrosis and sterile injury spill HMGB1 into the interstitial space, where it announces that tissue has been damaged. This makes HMGB1 a prototypical damage-associated molecular pattern, a class of endogenous molecules that alert the innate immune system to threat without requiring infection. The concept reframed inflammation as something the body triggers against itself: a heart attack, a crush injury, or an ischemic organ can all summon immune cells through HMGB1 alone. Its release is not merely a correlate of damage but a functional driver, because extracellular HMGB1 actively recruits neutrophils and monocytes and licenses the production of downstream inflammatory mediators. That sterile inflammation and infection share HMGB1 as a common upstream signal helps explain why tissue injury so often looks like infection at the cytokine level, and why blocking HMGB1 can dampen both.
Once outside the cell, HMGB1 does not act in isolation; it binds specific receptors that translate its presence into intracellular programs. The two best-characterized are Toll-like receptor 4 and the receptor for advanced glycation end products, and engagement of either activates the NF-κB pathway, the master switch of inflammatory gene expression. Through these receptors HMGB1 amplifies cytokine production, endothelial activation, and leukocyte recruitment, establishing positive feedback that can be useful in clearing threat but dangerous when unchecked. A critical modifier is redox state: the three conserved cysteines of HMGB1 can be reduced, oxidized, or disulfide-bonded, and only the fully reduced form exerts strong chemotactic activity, while oxidized HMGB1 loses immunogenic potency. This redox rheostat means the same protein can summon repair cells in one oxidation state and remain inert in another, allowing tissues to calibrate the alarm to the severity of injury. The elegance of the system is also its therapeutic opportunity, since agents that bind HMGB1 or block its receptors can extinguish inflammation without broadly suppressing immunity.
In oncology HMGB1 plays a genuinely paradoxical role, acting as both tumor promoter and suppressor depending on context. Within cancer cells, HMGB1 supports survival and chemoresistance: it induces autophagy that helps remaining cells endure cytotoxic therapy, and it can be overexpressed in aggressive tumors of the breast, lung, and colorectum where high levels often portend poor prognosis. Yet in other settings HMGB1 limits malignancy, and its expression correlates with immune infiltration that may restrain progression. The mechanistic picture is rich — HMGB1 modulates proliferation, invasion, metastasis, and the tumor immune microenvironment through pathways involving NF-κB, STAT3, PI3K, and autophagy regulators — and it has been proposed both as a diagnostic biomarker and as a target for sensitizing tumors to chemotherapy and immunotherapy. The challenge is specificity: because HMGB1 is so central to stress responses, interventions must distinguish the pro-tumor signals from the protective ones. Recent structural models of HMGB1 have begun to enable rational docking of anticancer compounds, raising the prospect of drugs that exploit its active sites without collapsing its housekeeping functions.
Figure 2. HMGB1 makes a metastatic microenvironment. (Source: Azizian-Farsani F, et al. 2020)
The liver has become a focal point for HMGB1 research because the organ sits at the crossroads of sterile and infectious injury. Extracellular HMGB1 has been implicated in acetaminophen toxicity, hepatic ischemia–reperfusion injury, and acute liver failure, where its release from parenchymal and non-parenchymal cells ignites neutrophil recruitment and worsens damage. In chronic liver disease, HMGB1 contributes to nonalcoholic fatty liver disease, alcohol-associated injury, fibrosis, and hepatocellular carcinoma, with post-translational modifications such as acetylation, phosphorylation, and lactylation tuning its translocation and inflammatory potency. Targeting HMGB1 — whether by blocking its release, neutralizing extracellular protein, or interfering with receptor binding — has shown promise in animal models of liver injury, supporting the idea that the alarm signal is not just a marker but a treatable contributor. The liver work is emblematic of a broader principle: in nearly every inflammatory disease examined, from arthritis to vasculitis, HMGB1 appears as both witness and accomplice.
HMGB1 has unexpectedly strong footing in the nervous system, where its release from microglia and astrocytes drives neuroinflammation and where its levels rise in stroke, neurodegeneration, and mood disorders. In experimental stroke, inhibition of the HMGB1–TLR4–NF-κB axis reduces oxidative stress and neuronal death, illustrating how a chromatin protein becomes a lever for brain injury. In psychiatry, chronic stress elevates HMGB1 in the medial prefrontal cortex, where it activates a STAT3–p65 axis in microglia that promotes both activation and autophagy and converges on depressive-like behavior; knocking down HMGB1 rescues the phenotype, positioning it as a candidate biomarker and therapeutic node for major depressive disorder. These findings connect two fields that rarely spoke — neuroimmunology and psychiatry — and suggest that the inflammatory alarm HMGB1 sounds in the periphery has a cognitive and emotional echo in the brain.
Aging reshapes HMGB1 in a consistent and instructive way: intracellular levels tend to fall while extracellular release rises, a pattern that dovetails with the chronic low-grade inflammation — inflammaging — that characterizes old tissues. Because HMGB1 orchestrates both inflammatory and regenerative programs, its shifting balance may simultaneously drive age-related pathology and attempt to compensate for it. Lower nuclear HMGB1 weakens genome-stability and repair functions precisely when they are most needed, while higher extracellular HMGB1 sustains a background alarm that wears tissues down. This has led to proposals that HMGB1 could serve as a universal biomarker of aging across diverse organs, and that modulating its release or redox state might promote healthy longevity. The appeal is that HMGB1 sits upstream of many hallmarks of aging at once — genomic instability, chronic inflammation, and failed repair — making it a rare single node through which several aging phenotypes converge.
The breadth of HMGB1 involvement has made it a magnet for therapeutic strategies, yet translation has been cautious. Approaches include neutralizing antibodies, soluble receptor decoys, small molecules that bind the B box, and natural products such as glycyrrhizin that interfere with HMGB1 activity. The conceptual advantage is selectivity for the damage-alarm pathway rather than blanket immune suppression, which is why HMGB1 antagonists have been explored in sepsis, ischemia, arthritis, and cancer sensitization. The principal obstacle is the protein's essential nuclear roles: any therapy must quench extracellular signaling without disabling DNA repair or transcription. Redox- and compartment-specific interventions — for example, agents that favor the inert oxidized state or that block receptor binding without entering the nucleus — represent the most plausible path forward, and ongoing work on HMGB1 structure continues to refine where and how to intervene.
References
| Target | Cat. No. | Product Name | Size | Species | Application | Detection Sample | |
| HMGB1 | DEIABL16 | Pig HMG1/HMGB1 ELISA Kit | 96T | Pig | Quantitative | Plasma, Serum | Inquiry |
| HMGB1 | DEIA-FB15 | Human HMGB1(High mobility group protein B1) ELISA Kit | 96T | Human | Quantitative | Serum, plasma, cell culture supernatant and other biological samples | Inquiry |
| HMGB1 | DEIA-FB16 | Rat Hmgb1(High mobility group protein B1) ELISA Kit | 96T | Rat | Quantitative | Serum, plasma, cell culture supernatant and other biological samples | Inquiry |
| HMGB1 | DEIA-FB17 | Mouse Hmgb1(High mobility group protein B1) ELISA Kit | 96T | Mouse | Quantitative | Serum, plasma, cell culture supernatant and other biological samples | Inquiry |
| HMGB1 | DEIA-FB18 | Rabbit HMGB-1 (High mobility group protein B1) ELISA Kit | 96T | Rabbit | Quantitative | Serum, plasma, tissue homogenates and other biological fluids | Inquiry |
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