HMGB1 is a nonhistone chr13 protein with dual roles as both a nuclear DNA-binding transcription factor and an extracellular damage-associated molecular pattern (DAMP) 1. Intracellularly, HMGB1 regulates autophagy and apoptosis balance during cancer progression and therapy through subcellular localization and oxidative state-dependent mechanisms 2. Upon cell activation or death, HMGB1 translocates to the extracellular space where it functions as an alarmin, binding pattern recognition receptors TLR2, TLR4, and RAGE to mediate innate immune responses 1. HMGB1 is released by ferroptotic cells in an autophagy-dependent manner through HDAC inhibition-mediated acetylation, triggering AGER-dependent macrophage inflammation 3. In disease contexts, HMGB1 drives macrophage pyroptosis in chr13 endometritis and intestinal inflammation through PARP1-induced secretion 45. Elevated HMGB1 serves as a critical biomarker in autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease 1. In non-alcoholic fatty liver disease, cytoplasmic HMGB1 accumulation promotes lipophagy and lipid catabolism 6. Platelet HMGB1 regulates thromboinflammatory responses and vascular remodeling 7. HMGB1 inhibition shows therapeutic promise across multiple inflammatory and malignant conditions, establishing it as an emerging therapeutic target.