{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHigh mobility group box 1 protein (HMGB1) is a multifunctional molecule that, under basal conditions, resides in the nucleus where it acts as an architectural chromatin‐binding protein facilitating transcription, DNA bending, and nucleosome stabilization. In response to cellular stress or stimulation, HMGB1 undergoes post‐translational modifications (e.g., acetylation) that favor its translocation from the nucleus to the cytoplasm and, subsequently, its extracellular release. Importantly, its mode of release differs depending on the mode of cell death: necrotic cells actively “broadcast” HMGB1 as an alarm signal, whereas apoptotic cells retain it via chromatin binding, thereby minimizing inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOnce in the extracellular milieu, HMGB1 functions as a prototypical damage‐associated molecular pattern (DAMP) that orchestrates inflammation and immune responses. It signals through receptors—most notably the receptor for advanced glycation end products (RAGE) and various Toll‐like receptors—to promote the expression of adhesion molecules, chemokines, and cytokines in endothelial cells and immune cells. HMGB1 can also form complexes with other mediators (for example, interleukin-1β, CXCL12, or LPS), thereby amplifying its proinflammatory potential and influencing dendritic cell and natural killer cell activation and maturation. In addition, HMGB1 supports the recruitment and activation of monocytes and facilitates transendothelial migration through interactions with integrins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHMGB1 is further implicated in regulating cell death and survival pathways. Its redox state critically determines whether it promotes autophagy—a prosurvival mechanism linked to chemoresistance—or triggers apoptotic and pyroptotic cell death via lysosomal disruption and caspase activation. HMGB1 can be released during ferroptosis and other forms of regulated necrosis, thereby not only acting as an inflammation mediator but also modulating immune tolerance through oxidative modification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, HMGB1 assumes a dual role by promoting processes that underpin many hallmarks of malignancy while, under certain conditions, contributing to tumor suppression. It supports tumor progression by enhancing mitochondrial complex I activity, ATP production, and autophagy—a mechanism that may underlie chemoresistance. Moreover, HMGB1 engages in cross-talk with tumor suppressor p53 and other signaling pathways, influencing cell survival, proliferation, immune escape, angiogenesis, and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, HMGB1 acts as a critical mediator in systemic inflammatory and vascular disorders. Elevated extracellular HMGB1 is associated with sepsis, ischemic stroke, and even pediatric vasculitides such as Kawasaki disease, where it not only propagates a robust inflammatory milieu via receptor interactions (e.g., with RAGE) but also modulates coagulation and endothelial barrier dysfunction. 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