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Immunol."],"abstract":"<jats:p>Sepsis is a life-threatening clinical syndrome characterized by high morbidity and mortality. In the pathogenesis of Gram-negative bacterial infection, lipopolysaccharide (LPS) functions as a critical pro-inflammatory toxin that initiates inflammatory and coagulation cascades through two principal receptor systems: Toll-like receptor 4 (TLR4), expressed on the cell surface and within endosomes, and the cytosolic inflammatory caspases \u2014 caspase-11 in mice and caspases-4 and -5 in humans. In the extracellular environment, LPS binds to high mobility group box 1 protein (HMGB1) to form an HMGB1\u2013LPS complex, which is internalized through receptor for advanced glycation end-products (RAGE)\u2013mediated endocytosis and trafficked to the lysosome. Within the acidic lysosomal compartment, HMGB1 permeabilizes the limiting membrane, enabling LPS to access and activate caspase-11. This cascade drives further HMGB1 release, amplifies inflammation and coagulopathy, and ultimately contributes to multi-organ failure. The observation that LPS-driven fulminant inflammation depends critically on HMGB1 cooperation has opened new therapeutic avenues directed at HMGB1 and has yielded encouraging results in preclinical models. However, no such strategy has yet been translated into clinical practice. In addition, HMGB1 can be actively released by peripheral sensory neurons following tissue injury, a mechanism now recognized as integral to the initiation and propagation of inflammation. The present review synthesizes current understanding of the reciprocal interactions between LPS and HMGB1 and considers emerging therapeutic opportunities in sepsis.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1862196","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:35:37Z","timestamp":1782448537000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipopolysaccharide and HMGB1: key regulatory factors in the pathophysiology of sepsis a mechanistic and therapeutic review"],"prefix":"10.3389","volume":"17","author":[{"given":"ZiAng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhengGang","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The 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