High mobility group box 1 (HMGB1)

Overview

HMGB1 (high-mobility group box 1) is a highly conserved nuclear protein that functions primarily as a chromatin-associated DNA-binding factor, but it is also widely recognized as an extracellular signaling molecule. In the nucleus, HMGB1 helps organize chromatin and modulate transcriptional accessibility. When released from stressed, damaged, or dying cells, it can act as an alarmin or damage-associated molecular pattern, promoting inflammatory signaling through receptors such as receptor for advanced glycation end products (RAGE) and, in broader inflammatory contexts, pathways involving toll like receptor 4 (TLR4).

In biomedical research, HMGB1 is frequently studied as a mediator of inflammation, tissue injury, and immunogenic cell death. Its extracellular release is often associated with immune activation, while intracellular regulation of HMGB1, including acetylation status and subcellular localization, can influence inflammatory outcomes. Because of these roles, HMGB1 has become a target of interest in cancer immunotherapy, sepsis, liver injury, disc degeneration, and neonatal inflammatory conditions.

Recent Publications Summary

Recent studies have continued to position HMGB1 as a multifunctional mediator in inflammation, cell stress, and treatment response across diverse disease settings. In polycystic ovary syndrome, HMGB1 was examined in the context of ovarian granulosa cell insulin resistance, where a long noncoding RNA, LUCAT1, was reported to alleviate insulin resistance by blocking HMGB1-mediated autophagy 42381638Jul. In neonatal jaundice, investigators measured serum HMGB1 together with sCD14 to assess associations with disease severity and phototherapy efficacy 42186388May. HMGB1 was also monitored longitudinally during neoadjuvant chemoradiotherapy in rectal cancer, reflecting interest in its use as a blood-based marker of immunogenic cell death and its correlation with MRI response and circulating tumor DNA 42359756Jun.

Several publications focused on HMGB1 in cancer therapy resistance and antitumor immunity. In colorectal cancer, HMGB1 was implicated in radioresistance through a pathway involving EFHD2, lactate-mediated DNA damage repair, and immunosuppression, with the study linking HMGB1 and HIF-1α to these processes 42336814Jun. In hepatocellular carcinoma, WNK4 was reported to promote anti-PD-1 resistance and tumor progression through reprogramming cysteine metabolism in cancer-associated fibroblasts, placing HMGB1-related inflammatory and microenvironmental signaling in the broader context of immunotherapy resistance 42253146Jun. A separate nanoplatform study used ultrasound-activated sonodynamic therapy with ratio-tunable dual peptides targeting CD47 and PD-L1; this approach induced immunogenic cell death with HMGB1 release and enhanced dendritic cell maturation in tumor models 41979280Apr.

Other studies linked HMGB1 to extracellular vesicle signaling and inflammatory tissue injury. In arthritis mice, joint-derived exosomes were shown to carry surface-displayed HMGB1 to the brain, where they activated neuronal NF-κB and cellular senescence programs associated with depressive-like behavior; neutralizing HMGB1 reduced these effects 42107473May. In intervertebral disc degeneration, bone marrow mesenchymal stem cell-derived exosomes were reported to ameliorate inflammation by regulating HMGB1 acetylation via SIRT6 41875702Mar. In cholestatic liver injury, naringenin nanosuspensions embedded in a glycyrrhizin-based hydrogel were described as improving liver injury by inhibiting oxidative stress and HMGB1-mediated inflammation 41576734Jan. HMGB1 was also studied in microglia in relation to electrostatic interactions with alarmin receptors, including RAGE and TLR4, in work evaluating dendrimeric polyglycerol systems 42081615May.

What Changes, What Holds

1. HMGB1 is emerging as a context-dependent biomarker and mechanistic node in metabolic, neonatal, and treatment-response settings
NEW DIRECTION These studies extend HMGB1 beyond its established inflammatory and injury roles into disease monitoring and pathway-specific modulation, including insulin resistance in ovarian granulosa cells, neonatal jaundice severity/phototherapy response, and longitudinal tracking during rectal cancer chemoradiotherapy 42381638Jul42186388May42359756Jun. That broadens its practical use as a circulating readout of stress and response, but the evidence is still application-specific rather than a unified new biology.

2. HMGB1 remains a plausible mediator of therapy resistance and antitumor immune activation, but the new work is mostly mechanistic refinement
REINFORCES The colorectal and hepatocellular carcinoma studies fit the established view of HMGB1 as part of inflammatory and immunotherapy-relevant signaling, while the sonodynamic therapy report again uses HMGB1 release as a marker and effector of immunogenic cell death 42336814Jun42253146Jun41979280Apr. What changes is not the core role of HMGB1, but the detail of how it is embedded in resistance circuits and treatment-induced immune priming.

3. HMGB1 is now being linked to extracellular vesicle trafficking and remote neuroinflammatory effects, expanding its injury biology into inter-organ signaling
NEW DIRECTION Joint exosomes carrying surface HMGB1 to the brain, exosome-mediated control of HMGB1 acetylation in disc degeneration, and HMGB1-targeted anti-inflammatory nanotherapy in cholestatic liver injury all sit outside the baseline’s chromatin and general extracellular alarmin framing 42107473May41875702Mar41576734Jan. The microglia work further supports receptor-level inflammatory signaling, but the main update is that HMGB1 is being treated as a transferable cargo and a modifiable extracellular axis, not only a released danger signal.

Overview update candidates: HMGB1 as a biomarker in treatment response and neonatal disease; HMGB1 in extracellular vesicle-mediated inter-organ signaling; HMGB1 acetylation as a therapeutic control point.