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HMGB1 (high mobility group box 1) is a multifunctional, ubiqui-tous protein located inside and outside cells that plays a critical role in various physiological and pathological processes including cell development, differentia-tion, inflammation, immunity, metas-tasis, metabolism, and death. Increasing evidence demonstrates that HMGB1-dependent autophagy promotes che-motherapy resistance, sustains tumor metabolism requirements and T cell survival, prevents polyglutamine aggre-gates and excitotoxicity, and protects against endotoxemia, bacterial infec-tion, and ischemia-reperfusion injury i