HMGB

High-mobility group box 1 (HMGB1) is an evolutionarily conserved non-histone nuclear protein that functions as a DNA chaperone, chromosome guardian, and regulator of autophagy and apoptosis^[1]. Mechanistically, HMGB1 translocates to the cytoplasm under stress or hyperacetylation and is actively secreted extracellularly, where it acts as a prototypic damage-associated molecular pattern (DAMP) molecule^[2][3]. Extracellular HMGB1 engages multiple receptors including Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), triggering NF-κB and MAPK signaling, thereby promoting inflammatory cytokine release and modulating immune cell activity^[4][5][1]. Compared with related isoforms in the HMG family, HMGB1 exhibits unique redox-sensitive cysteine residues that determine its extracellular proinflammatory or immunoregulatory activity^[2][3]. In disease models, HMGB1 contributes to liver injury, chronic prostatitis, ureteral stricture, sepsis, hypoxic-ischemic brain damage, and tumor progression via modulation of macrophage polarization, T cell suppression, and fibroblast activation^{[6][7][8][9][10]}. Pharmacological inhibition of HMGB1 using small molecules, peptides, glycyrrhizin, or antibodies attenuates inflammatory responses, reduces tissue damage, and restores homeostasis in preclinical models^{[6][11][8][12]}. Agonist studies reveal that exogenous HMGB1 can rescue apoptosis and enhance proliferation in specific cell types through RAGE/TLR4-PI3K/ERK pathways, indicating its context-dependent functional versatility^[13]. Overall, HMGB1 serves as a central mediator of cellular stress responses, inflammation, and immune regulation, making it a critical target for experimental and therapeutic applications^[1][14].