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.

Key Publications

NEWJun WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42253146): "According to mechanism investigation, WNK4 could bind high mobility group box 1 (HMGB1) and induce its phosphorylation and cytoplasmic retention, thus reducing nuclear HMGB1-p53 interaction to enhance cystathionine gamma-lyase (CTH) expression."
Mar Layered double hydroxide nanoplatform synergizes with sonodynamic therapy to induce dual activation of cuproptosis and ferroptosis for breast cancer treatment. (Bioorganic chemistry, 2026, PMID 41830770): "Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity."
May Triterpenoids from quinoa bran exert anti-colorectal cancer effects via oxidative stress-mediated apoptosis and immune reactivation. (Food & function, 2026, PMID 42093524): "as evidenced by enhanced calreticulin exposure and the release of ATP and high mobility group box 1 (HMGB1), eliciting a robust "vaccine-like effect"."
May Serum HMGB1 and sCD14 levels in neonates with jaundice: associations with disease severity and phototherapy efficacy. (The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 2026, PMID 42186388): "To investigate the associations of serum high-mobility group box-1 (HMGB1) and soluble cluster of differentiation antigen-14 (sCD14) with disease severity in neonatal jaundice, and to explore their relationship with phototherapy response."
May Bone marrow mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration by regulating HMGB1 acetylation via SIRT6. (Biochemical and biophysical research communications, 2026, PMID 41875702): "BMSC-exos might alleviate IVDD by promoting SIRT6-mediated deacetylation of high mobility group box 1 (HMGB1), thereby suppressing inflammation."
May Dually Charged Dendrimeric Polyglycerol Modulates Interleukin-33 at Alarmin Receptors in Microglia. (ACS chemical neuroscience, 2026, PMID 42081615): "...heparan sulfate interaction with the alarmin high mobility group box 1 (HMGB1) is critical for receptor for advanced glycation end products (RAGE)-mediated signaling."
May Rosmarinic acid/Se4+ self-assembled nanoparticles for combinational therapy of triple-negative breast cancer. (Biomaterials advances, 2026, PMID 41512467): "Beyond inducing potent apoptosis in cancer cells, RA-Se@M triggered robust immunogenic cell death (ICD), as evidenced by calreticulin exposure, HMGB1 release, and dendritic cell maturation."
May Naringenin nanosuspensions embedded glycyrrhizin-based hydrogel ameliorates cholestatic liver injury in mice by inhibiting oxidative stress and HMGB1-mediated inflammation. (Colloids and surfaces. B, Biointerfaces, 2026, PMID 41576734): "Mechanistic investigations revealed for the first time that HMGB1 signaling is involved in this cholestatic liver injury, and NanoNAR@Glycygel exerted its potent therapeutic effect by inhibiting this signaling."
May Selenium nanoparticles as adjunctive therapy in sepsis: A pilot randomized clinical trial. (Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2026, PMID 41825095): "SeNPs supplementation was also associated with reduced inflammation, as indicated by lower levels of pro-inflammatory cytokines IL-6 and HMGB1."
Apr Ratio-Tunable Dual-Peptide and Ultrasound-Assisted Nanoplatform for Enhancing Personalized Antitumor Immunotherapy. (Advanced materials (Deerfield Beach, Fla.), 2026, PMID 41979280): "ultrasound-activated sonodynamic therapy generates reactive oxygen species to induce immunogenic cell death with calreticulin exposure and ATP and HMGB1 release."