Linghong Guo, Daihan Wang, Xian Jiang, Gu He
High Mobility Group Box 1 (HMGB1) is a nuclear protein crucial for nucleosome stability, gene regulation, DNA repair, cell differentiation, and development. Extracellularly, HMGB1 functions as a cytokine, significantly impacting inflammation, immune response, and the pathogenesis of various diseases, including cancer and inflammatory disorders. Research highlights HMGB1's complex role in cancer, where it promotes tumorigenesis through chronic inflammation and immune suppression while enhancing chemotherapy and genome stability. It also influences cell proliferation, angiogenesis, metastasis, and chemotherapy resistance. In inflammatory diseases, HMGB1 has a dual role: it can promote inflammation in conditions like ischemia-reperfusion injury and sepsis but also induces immune tolerance and suppression. This review provides a comprehensive overview of HMGB1's structure, functions, and regulatory mechanisms, discussing recent advances in understanding its roles in cancer and inflammatory diseases. We emphasize the evolving therapeutic strategies targeting HMGB1, underscoring its potential as a promising target for treating both cancer and inflammatory disorders.