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 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.

Focus of Latest Publications

Recent publications have examined HMGB1 in diverse disease contexts, with a strong emphasis on inflammation, cancer, and treatment response. In neonatal jaundice, serum HMGB1 and soluble CD14 (sCD14) were investigated for associations with disease severity and phototherapy efficacy, indicating interest in HMGB1 as a circulating inflammatory marker in newborns with hyperbilirubinemia. In this setting, HMGB1 was studied alongside sCD14 to assess whether systemic immune activation correlates with clinical severity and response to light therapy.

In oncology, HMGB1 has appeared repeatedly as a mechanistic node in tumor progression and antitumor immunity. A study in hepatocellular carcinoma reported that WNK4 binds HMGB1 and induces its phosphorylation and cytoplasmic retention, thereby reducing nuclear HMGB1-p53 interaction and increasing cystathionine gamma-lyase (CTH) expression. This suggests that HMGB1 localization and post-translational regulation can influence cancer-associated fibroblast metabolism and contribute to anti-PD-1 resistance and tumor progression. In another cancer study, triterpenoids from quinoa bran were reported to exert anti-colorectal cancer effects through oxidative stress-mediated apoptosis and immune reactivation, with HMGB1 release serving as part of a “vaccine-like effect” consistent with immunogenic cell death. Similarly, rosmarinic acid/Se4+ self-assembled nanoparticles in triple-negative breast cancer triggered immunogenic cell death, evidenced by calreticulin exposure, HMGB1 release, and dendritic cell maturation. A related nanoplatform using zinc-copper-iron-based layered double hydroxide with sonodynamic therapy also induced immunogenic cell death characterized by HMGB1 release and dendritic cell maturation, supporting a role for HMGB1 as a marker and mediator of antitumor immune activation.

HMGB1 has also been studied in inflammatory and degenerative disease models. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) were reported to alleviate intervertebral disc degeneration by promoting SIRT6-mediated deacetylation of HMGB1, thereby suppressing inflammation. This highlights the importance of HMGB1 acetylation status in controlling its inflammatory activity and subcellular localization. In cholestatic liver injury, naringenin nanosuspensions embedded in a glycyrrhizin-based hydrogel were found to ameliorate injury by inhibiting oxidative stress and HMGB1-mediated inflammation, with the authors noting that HMGB1 signaling was involved in the disease process and that NanoNAR@Glycygel exerted therapeutic effects by suppressing this pathway. In sepsis, a pilot randomized clinical trial of selenium nanoparticles reported reduced inflammation, including lower HMGB1 levels, suggesting that HMGB1 may track systemic inflammatory burden in critically ill patients.

Additional mechanistic work has linked HMGB1 to receptor-level signaling and extracellular matrix interactions. One study on alarmin receptors in microglia noted that heparan sulfate interaction with HMGB1 is critical for RAGE-mediated signaling, reinforcing the role of HMGB1 as an extracellular inflammatory ligand in the nervous system. Across these studies, HMGB1 consistently appears as a central mediator of stress responses, inflammation, and immune modulation, with relevance to cancer immunotherapy, tissue injury, and biomarker development.