{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:43:24Z","timestamp":1793371404848,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The pathological process of type 2 diabetes mellitus (T2DM) is closely associated with chronic low\u2212grade inflammation. High mobility group box 1 (HMGB1), a key damage\u2212associated molecular pattern (DAMP), is frequently dysregulated in T2DM and is implicated in promoting insulin resistance (IR), \u03b2 cell dysfunction, and the progression of multiple complications\u2014including cardiovascular disease, nephropathy, cognitive impairment, myopathy, and dyslipidemia\u2014primarily through activating signaling pathways such as RAGE\/TLR4\u2212NF\u2212\u03baB. Exercise, a cornerstone non\u2212pharmacological intervention, effectively mitigates HMGB1\u2212driven pathology through multifaceted mechanisms. These include direct downregulation of HMGB1 expression and suppression of its downstream inflammatory pathways, as well as indirect effects via improved glycemic control, enhancing autophagy, and reduced oxidative stress. This review aims to systematically examine the evidence for the role of HMGB1 in T2DM pathogenesis and its complications, and to evaluate exercise as a potential strategy to target this inflammatory pathway, thereby providing a theoretical framework for future therapeutic approaches.<\/jats:p>","DOI":"10.3389\/fendo.2026.1769497","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:52:44Z","timestamp":1772175164000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["HMGB1: a key molecule linking chronic inflammation to complications in type 2 diabetes mellitus and a target for exercise intervention"],"prefix":"10.3389","volume":"17","author":[{"given":"Fu","family":"Pengyu","sequence":"first","affiliation":[{"name":"Department of Physical Education, Northwestern Polytechnical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Huiyun","sequence":"additional","affiliation":[{"name":"College of Life Sciences and Technology, Northwestern Polytechnical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Lijing","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Physical Fitness, Ministry of Education, Beijing Sport University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6275","DOI":"10.3390\/ijms21176275","article-title":"Pathophysiology of type 2 diabetes mellitus","volume":"21","author":"Galicia-Garcia","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1603484","article-title":"Meta-inflammation in type 2 diabetes mellitus: unveiling the role of aberrant CD4(+) T cells and pro-inflammatory cytokine networks","volume":"16","author":"Shaw","year":"2025","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.3390\/ijms26031094","article-title":"Type 2 diabetes mellitus: new pathogenetic mechanisms, treatment and the most important complications","volume":"26","author":"M\u0142ynarska","year":"2025","journal-title":"Int J Mol Sci."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2014.55.5.1165","article-title":"The role of high mobility group box 1 in innate immunity","volume":"55","author":"Lee","year":"2014","journal-title":"Yonsei Med J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e23561","article-title":"Restoring glucose balance: Conditional HMGB1 knockdown mitigates hyperglycemia in a Streptozotocin induced mouse model","volume":"10","author":"Liu","year":"2024","journal-title":"Heliyon"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S6","DOI":"10.2119\/molmed.2015.00087","article-title":"High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule","volume":"21","author":"Yang","year":"2015","journal-title":"Mol Med"},{"key":"B7","article-title":"HMGB1 is activated in type 2 diabetes mellitus patients and in mesangial cells in response to high glucose","volume":"8","author":"Chen","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1141516","article-title":"The relationship between HMGB1 and autophagy in the pathogenesis of diabetes and its complications","volume":"14","author":"Yang","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"100031","DOI":"10.1016\/j.ajmo.2023.100031","article-title":"The importance of exercise for glycemic control in type 2 diabetes","volume":"9","author":"Syeda","year":"2023","journal-title":"Am J Med Open"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2019.10225","article-title":"Fr\u2212HMGB1 and ds\u2212HMGB1 activate the kynurenine pathway via different mechanisms in association with depressive\u2212like behavior","volume":"20","author":"Wang","year":"2019","journal-title":"Mol Med Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.gde.2005.08.007","article-title":"HMG proteins: dynamic players in gene regulation and differentiation","volume":"15","author":"Bianchi","year":"2005","journal-title":"Curr Opin Genet Dev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.3390\/cells9071664","article-title":"High mobility group box 1 in human cancer","volume":"9","author":"Rapoport","year":"2020","journal-title":"Cells"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2025.1600596","article-title":"Involvement of role of HMGB1-NLRP3 pathway in systemic disorders","volume":"13","author":"Yang","year":"2025","journal-title":"Front Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1016\/j.jid.2019.03.1148","article-title":"Oxidative stress-induced HMGB1 release from melanocytes: A paracrine mechanism underlying the cutaneous inflammation in vitiligo","volume":"139","author":"Cui","year":"2019","journal-title":"J Invest Dermatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2018.9584","article-title":"Effects of mimicked acetylated HMGB1 on macrophages and dendritic cells","volume":"18","author":"Chen","year":"2018","journal-title":"Mol Med Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41419-019-1413-8","article-title":"Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors","volume":"10","author":"Yang","year":"2019","journal-title":"Cell Death Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.12.7506","article-title":"Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products","volume":"174","author":"Dumitriu","year":"2005","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2543268","DOI":"10.1155\/2016\/2543268","article-title":"The role of HMGB1 in the pathogenesis of type 2 diabetes","volume":"2016","author":"Wang","year":"2016","journal-title":"J Diabetes Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"100023","DOI":"10.1016\/j.lddd.2025.100023","article-title":"An update on the role of inflammation in insulin resistance and islet \u03b2 cell failure- A crosstalk between immune cells, adipose tissue, cytokines, and oxidative stress","volume":"22","author":"Venkatesan","year":"2025","journal-title":"Lett Drug Design Discov"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/2025.04.27.650052","article-title":"Exercise conditioning enhances insulin sensitivity with metabolic and glycemic control driven by hepatic silencing of HMGB1 in type 2 diabetic mice","author":"Bravo","year":"2025","journal-title":"bioRxiv"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1515\/jbcpp-2020-0442","article-title":"Analysis of HMGB-1 level before and after providing atorvastatin standard therapy in coronary artery disease patients with type-2 diabetes mellitus compared to without type-2 diabetes mellitus","volume":"32","author":"Handayani","year":"2021","journal-title":"J basic Clin Physiol Pharmacol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20246258","article-title":"High mobility group box-1 and diabetes mellitus complications: state of the art and future perspectives","volume":"20","author":"Biscetti","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"115118","DOI":"10.1016\/j.biopha.2023.115118","article-title":"HMGB family proteins: Potential biomarkers and mechanistic factors in cardiovascular diseases","volume":"165","author":"Zheng","year":"2023","journal-title":"Biomedicine Pharmacotherapy"},{"key":"B24","doi-asserted-by":"publisher","first-page":"108834","DOI":"10.1016\/j.isci.2024.108834","article-title":"Investigating HMGB1 as a potential serum biomarker for early diabetic nephropathy monitoring by quantitative proteomics","volume":"27","author":"Peng","year":"2024","journal-title":"iScience"},{"key":"B25","doi-asserted-by":"publisher","first-page":"8743","DOI":"10.3390\/ijerph19148743","article-title":"Glycyrrhizic acid attenuates pulmonary fibrosis of silicosis by inhibiting the interaction between HMGB1 and BRG1 through PI3K\/Akt\/mTOR pathway","volume":"19","author":"Niu","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6258","DOI":"10.1007\/s00210-025-04681-z","article-title":"Irisin attenuates tubular epithelial ferroptosis in diabetic kidney disease by inhibiting the HMGB1\/Nrf2\/GPX4 pathway","author":"Wang","year":"2025","journal-title":"Naunyn-Schmiedeberg\u2019s Arch Pharmacol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04081-z","article-title":"High mobility group box protein (HMGB1): A potential therapeutic target for diabetic encephalopathy","volume":"61","author":"Dash","year":"2024","journal-title":"Mol Neurobiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"112933","DOI":"10.1016\/j.biopha.2022.112933","article-title":"HMGB1 signaling pathway in diabetes-related dementia: Blood-brain barrier breakdown, brain insulin resistance, and A\u03b2 accumulation","volume":"150","author":"Jeong","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B29","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.jneuroim.2021.577763","article-title":"HMGB1 plays an important role in pyroptosis induced blood brain barrier breakdown in diabetes-associated cognitive decline","volume":"362","author":"Liu","year":"2022","journal-title":"J Neuroimmunology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12662","article-title":"Amelioration of diabetes-induced inflammation mediated pyroptosis, sarcopenia, and adverse muscle remodelling by bone morphogenetic protein-7","volume":"12","author":"Aluganti Narasimhulu","year":"2021","journal-title":"J cachexia sarcopenia Muscle"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-025-09954-9","article-title":"Skeletal muscle atrophy and dysfunction in obesity and type-2 diabetes mellitus: Myocellular mechanisms involved","volume":"26","author":"Castillo \u00cd","year":"2025","journal-title":"Rev endocrine Metab Disord"},{"key":"B32","doi-asserted-by":"publisher","first-page":"111417","DOI":"10.1016\/j.mce.2021.111417","article-title":"The potential role of the adipokine HMGB1 in obesity and insulin resistance. Novel effects on adipose tissue biology","volume":"536","author":"Guzm\u00e1n-Ruiz","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"4222","DOI":"10.3390\/ijms26094222","article-title":"HMGB1 regulates adipocyte lipolysis via caveolin-1 signaling: implications for metabolic and cardiovascular diseases","volume":"26","author":"Hsu","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3889\/oamjms.2021.7199","article-title":"High-glucose and free fatty acid-induced adipocytes generate increasing of HMGB1 and reduced GLUT4 expression","volume":"9","author":"Rosita","year":"2021","journal-title":"Open Access Macedonian J Med Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13251","article-title":"An accumulation of muscle macrophages is accompanied by altered insulin sensitivity after reduced activity and recovery","volume":"226","author":"Reidy","year":"2019","journal-title":"Acta physiologica (Oxford England)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10565-024-09893-2","article-title":"HMGB1 as an extracellular pro-inflammatory cytokine: Implications for drug-induced organic damage","volume":"40","author":"Yuan","year":"2024","journal-title":"Cell Biol Toxicol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"14791641241271949","DOI":"10.1177\/14791641241271949","article-title":"The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target","volume":"21","author":"Ngcobo","year":"2024","journal-title":"Diabetes Vasc Dis Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2010.158030","article-title":"Short-term treadmill running as a model for studying cell-free DNA kinetics in vivo","volume":"57","author":"Beiter","year":"2011","journal-title":"Clin Chem"},{"key":"B39","doi-asserted-by":"publisher","first-page":"31396","DOI":"10.31083\/FBL31396","article-title":"High-intensity interval training decreases circulating HMGB1 in individuals with insulin resistance: plasma lipidomics correlate with associated cardiometabolic benefits","volume":"30","author":"Martinez Bravo","year":"2025","journal-title":"Front bioscience (Landmark edition)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.06.031","article-title":"Exercise alarms the immune system: A HMGB1 perspective","volume":"110","author":"Goh","year":"2018","journal-title":"Cytokine"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.31838\/srp.2020.4.44","article-title":"Research reviews on effect of exercise on DAMP\u2019s, HMGB1, proinflammatory cytokines and leukocytes","volume":"11","author":"Pattelongi","year":"2020","journal-title":"Sys Rev Pharm"},{"key":"B42","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s41231-020-00056-z","article-title":"Concurrent high-intensity aerobic and resistance exercise modulates systemic release of alarmins (HMGB1, S100A8\/A9, HSP70) and inflammatory biomarkers in healthy young men: a pilot study","volume":"5","author":"Goh","year":"2020","journal-title":"Trans Med Commun"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s42978-022-00182-0","article-title":"The role of autophagy regulator HMGB1 in skeletal muscle autophagy after eccentric exercise","volume":"5","author":"Li","year":"2023","journal-title":"J Sci Sport Exercise"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/med.70017","article-title":"HMGB1: from molecular functions to clinical applications in cancer and inflammatory diseases","volume":"46","author":"Guo","year":"2025","journal-title":"Med Res Rev"},{"key":"B45","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.freeradbiomed.2023.07.031","article-title":"Effects of different doses of exercise in adjunct to diet-induced weight loss on the AGE-RAGE axis in patients with short standing type 2 diabetes: Secondary analysis of the DOSE-EX multi-arm, parallel-group, randomised trial","volume":"208","author":"Legaard","year":"2023","journal-title":"Free Radical Bio Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2020.09.015","article-title":"Treadmill exercise mitigates neuroinflammation and increases BDNF via activation of SIRT1 signaling in a mouse model of T2DM","volume":"165","author":"Lang","year":"2020","journal-title":"Brain Res Bull"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.965366","article-title":"Aerobic exercise alleviates pyroptosis-related diseases by regulating NLRP3 inflammasome","volume":"13","author":"Hu","year":"2022","journal-title":"Front Physiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00033.2024","article-title":"A comprehensive view of muscle glucose uptake: regulation by insulin, contractile activity, and exercise","volume":"105","author":"Richter","year":"2025","journal-title":"Physiol Rev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"18853","DOI":"10.1038\/s41598-025-03642-z","article-title":"GLUT1-mediated HMGB1 O-GlcNAcylation drives hyperglycemia-Induced neutrophil extracellular trap networks formation via TLR4 signaling and exacerbates fibroblast inflammation","volume":"15","author":"Sun","year":"2025","journal-title":"Sci Rep"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2024.12.036","article-title":"Exercise-driven cellular autophagy: A bridge to systematic wellness","volume":"76","author":"Zhou","year":"2025","journal-title":"J Advanced Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4196\/kjpp.24.240","article-title":"Functional interplay between non-canonical inflammasomes and autophagy in inflammatory responses and diseases","volume":"29","author":"Yi","year":"2025","journal-title":"Korean J Physiol Pharmacol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"25544","DOI":"10.31083\/FBL25544","article-title":"The role of HMGB1 in infection-related cognitive deficits","volume":"30","author":"Irzan","year":"2025","journal-title":"Front bioscience (Landmark edition)"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2200204","DOI":"10.1002\/adbi.202200204","article-title":"Moderate-intensity exercise maintains redox homeostasis for cardiovascular health","volume":"7","author":"Jiang","year":"2023","journal-title":"Adv Biol (Weinh)"},{"key":"B54","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/s12276-022-00736-w","article-title":"The mechanism of HMGB1 secretion and release","volume":"54","author":"Chen","year":"2022","journal-title":"Exp Mol Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1230646","article-title":"Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications","volume":"14","author":"Li","year":"2023","journal-title":"Front Endocrinol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/s41420-021-00746-z","article-title":"Moderate-intensity exercise alleviates pyroptosis by promoting autophagy in osteoarthritis via the P2X7\/AMPK\/mTOR axis","volume":"7","author":"Li","year":"2021","journal-title":"Cell Death Discov"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.202400761","article-title":"HMGB1 derived from the pyroptotic microenvironment promotes macrophage extracellular traps in hirschsprung-associated enterocolitis","volume":"9","author":"Zhang","year":"2025","journal-title":"Adv Biol (Weinh)"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1769497\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:52:45Z","timestamp":1772175165000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1769497\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,27]]},"references-count":57,"alternative-id":["10.3389\/fendo.2026.1769497"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1769497","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,27]]},"article-number":"1769497"}}