A Janus Tale of Two Active High Mobility Group Box 1 (HMGB1) Redox States
Open accessAbstract
High mobility group box 1 (HMGB1), the prototypic damage-associated molecular pattern molecule, is released at sites of inflammation and/or tissue damage. There, it promotes cytokine production and chemokine production/cell migration. New work shows that the redox status of HMGB1 distinguishes its cytokine-inducing and chemokine activity. Reduced all-thiol-HMGB1 has sole chemokine activity, whereas disulfide-HMGB1 has only cytokine activity, and oxidized, denatured HMGB1 has neither. Autophagy (programmed cell survival) and apoptosis (programmed cell death) have been implicated in controlling both innate and adaptive immune functions. Reduced HMGB1 protein promotes autophagy, whereas oxidized HMGB1 promotes apoptosis. Thus, the differential activity of HMGB1 in immunity, inflammation and cell death depends on the cellular redox status within tissues.
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HMGB1 biological activities can switch from pro-inflammatory to anti-inflammatory depending on variables including oxidation state.
“That said, it should be noted that biological activities of HMGB1 may flip from pro-inflammatory to anti-inflammatory depending on multiple variables including its oxidation state [917–923].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [917]
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Self-citationFerroptosis: friend or foe in cancer immunotherapy?
Demuynck, R., Efimova, I., Catanzaro, E., & Krysko, D. V. (2023) · OncoImmunology · doi:10.1080/2162402x.2023.2182992 · Cited by 19 · see citing works
Huang, Y.-H., Zhang, R., Lyu, H., Xiao, S., Guo, D. S., Chen, X., Zhou, C., & Tang, J. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.91832 · Cited by 18 · see citing works
Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex
Rafikov, R., Rischard, F. P., Vasilyev, M., Varghese, M. V., Yuan, J. X. ‐., Desai, A. A., Garcia, J. G. N., & Rafikova, O. (2022) · Translational research · doi:10.1016/j.trsl.2022.03.013 · Cited by 18 · see citing works
Inflachromene inhibits intimal hyperplasia through the HMGB1/2- regulated TLR4-NF-κB pathway
Teng, S., Zhu, Z., Wu, C., He, Y., & Zhou, S. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110198 · Cited by 16 · see citing works
Inflammatory responses in early pregnancy: Physiological and pathological perspectives
Negishi, Y., & Morita, R. (2024) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12619 · Cited by 17 · see citing works
Nolfi‐Donegan, D., Annarapu, G. K., Croix, C. M. S., Calderon, M. J., Hillery, C. A., & Shiva, S. (2024) · JCI Insight · doi:10.1172/jci.insight.174575 · Cited by 14 · see citing works
Elfeky, M., Yoneshiro, T., Okamatsu‐Ogura, Y., & Kimura, K. (2017) · The Journal of Biochemistry · doi:10.1093/jb/mvx069 · Cited by 14 · see citing works
Sasaki, R., Luo, Y., Kishi, S., Ogata, R., Nishiguchi, Y., Sasaki, T., Ohmori, H., Fujiwara‐Tani, R., & Kuniyasu, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031192 · Cited by 14 · see citing works
Fisher, R., Matheny, L., Ankeny, S. E., Qin, L., Coleman, L. G., & Vetreno, R. P. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1531628 · Cited by 13 · see citing works
Emerging landscape of non‐coding RNA s in oral health and disease
Pérez, P., Jang, S., & Alevizos, I. (2013) · Oral Diseases · doi:10.1111/odi.12142 · Cited by 11 · see citing works
Reed, K. R., Song, F., Young, M. A., Hassan, N., Antoine, D. J., Gemici, N.-P. B., Clarke, A. R., & Jenkins, J. R. (2016) · Oncotarget · doi:10.18632/oncotarget.10076 · Cited by 11 · see citing works
Min, H. J., Choe, J.-Y., Kim, K. S., Yoon, J.-H., & Kim, C. (2020) · Rhinology Journal · doi:10.4193/rhin18.281 · Cited by 10 · see citing works
Topa, E., Vurallı, D., Usta, D. D., Çalıkuşu, A., Yığman, Z., & Bolay, H. (2025) · The Journal of Headache and Pain · doi:10.1186/s10194-025-02191-0 · Cited by 9 · see citing works
Epochal neuroinflammatory role of high mobility group box 1 in central nervous system diseases
Richard, S. A., Min, W., Su, Z., & Xu, H. (2017) · AIMS molecular science · doi:10.3934/molsci.2017.2.185 · Cited by 9 · see citing works
Wei, T., Liu, J., Li, C., Tan, Y., Wei, R., Wang, J., Wu, H., Li, Q., Liu, H., Tang, Y., et al. (2023) · Chemical Science · doi:10.1039/d3sc01109g · Cited by 8 · see citing works
Su, T., Li, C., Zhang, Y., Yue, L., Chen, Y., Qian, X., & Shi, S. (2022) · FEBS Open Bio · doi:10.1002/2211-5463.13533 · Cited by 6 · see citing works
Kang, R., & Tang, D. (2016) · Springer eBooks · doi:10.1007/978-3-319-30079-5_5 · Cited by 6 · see citing works
Self-citationFestoff, B. W., & Dockendorff, C. (2021) · Biomolecules · doi:10.3390/biom11111558 · Cited by 5 · see citing works
HMGB1: a potential new target for tendinopathy treatment
Lu, P., Li, Y., Dai, G.-C., Zhang, Y., Shi, L., Zhang, M., Wang, H., & Rui, Y. (2023) · Connective Tissue Research · doi:10.1080/03008207.2023.2199089 · Cited by 5 · see citing works
Richard, S. A. (2018) · AIMS molecular science · doi:10.3934/molsci.2018.4.183 · Cited by 4 · see citing works
Land, W. G., & Linkermann, A. (2025) · Frontiers in Transplantation · doi:10.3389/frtra.2025.1571516 · Cited by 3 · see citing works
Gacaferi, H., Mimpen, J. Y., Baldwin, M. J., Snelling, S. J. B., Nelissen, R. G. H. H., Carr, A. J., & Dakin, S. G. (2020) · Translational Sports Medicine · doi:10.1002/tsm2.175 · Cited by 3 · see citing works
Min, H. J., Park, J. S., Kim, K. S., Kang, M., Seo, J. H., Yoon, J., Kim, C., & Cho, H. (2021) · Brazilian Journal of Otorhinolaryngology · doi:10.1016/j.bjorl.2020.11.019 · Cited by 3 · see citing works
The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1
Borde, C., Dillard, C., L’honoré, A., Quignon, F., Hamon, M., Marchand, C. H., Faccion, R. S., Costa, M. G. S., Pramil, É., Larsen, A. K., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147865 · Cited by 3 · see citing works
Tang, D., & Kang, R. (2015) · InTech eBooks · doi:10.5772/61208 · Cited by 3 · see citing works
Self-citationWang, J., Sato, A., Fujimori, H., Miki, Y., & Masutani, M. (2015) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-14151-0_5 · Cited by 3 · see citing works
HMGB1 signalling in Alzheimer’s disease: pathogenic roles and therapeutic prospects
Tyagi, P., Kumari, S., Sharma, P., Dhapola, R., Paidlewar, M., Medhi, B., & HariKrishnaReddy, D. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117204 · Cited by 2 · see citing works
Saha, A., Islam, M. M., Kumar, R., Ismail, A. M., Garcia, E., Gullapalli, R. R., Chodosh, J., & Rajaiya, J. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013184 · Cited by 2 · see citing works
Zhao, D., Ji, Q., Zhu, S., Zhu, K., & WANG, C. (2020) · Biocell · doi:10.32604/biocell.2020.09169 · Cited by 2 · see citing works
Peroxiredoxin 1, pyroptosis, and the emerging frontier in colorectal cancer therapy
Maurya, D. K. (2026) · World Journal of Gastroenterology · doi:10.3748/wjg.v32.i1.114184 · Cited by 2 · see citing works
- Authors
- Tang, D., Billiar, T. R., & Lotze, M. T.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Tang, Daolin
- Venue
- Molecular Medicine
- Published
- 2012-10
- Volume
- 18
- Issue
- 10
- Pages
- 1360-1362
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC3533642
- OpenAlex
- W224680839
- Cited by
- 112
- References
- 20
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 16 · 2014: 13 · 2013: 12
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- creativecommons.org/licenses/by/4.0 (tdm)
- Locations
- Molecular Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health
- National Cancer Institute (R01CA160417)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- HMGB1, redox state, disulfide bonds, damage-associated molecular patterns, chemokine activity, cytokine production, autophagy, apoptosis, inflammation, innate immunity, protein oxidation
- MeSH terms
- Animals, Disease, Humans, Oxidation-Reduction, Reactive Oxygen Species, HMGB1 Protein
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