Table1_HMGB1 is a mediator of cuproptosis-related sterile inflammation.XLSX

Cuproptosis is a recently recognized modality of cell death driven by intracellular copper-dependent mitochondrial stress. However, the mediators of the sterile inflammatory response to cuproptotic death are undetermined. Here, we report that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern, is released by cuproptotic cells to initiate inflammation. Mechanically, copper accumulation-induced adenosine triphosphate (ATP) depletion activates AMP-activated protein kinase (AMPK) to promote HMGB1 phosphorylation, resulting in increased extracellular release. In contrast, genetic (using RNAi) or pharmacologic (using dorsomorphin) inhibition of AMPK activation limits cuproptosis and HMGB1 release. Functionally, the ability of HMGB1-deficient cuproptotic cells to promote advanced glycosylation end product-specific receptor (AGER, also known as RAGE)-dependent inflammatory cytokine production is greatly reduced. Thus, HMGB1 is a key immune mediator of cuproptosis-initiated sterile inflammation.

铜死亡（Cuproptosis）是近年来被证实的一种由细胞内铜依赖性线粒体应激驱动的细胞死亡方式。然而，铜死亡诱导的无菌性炎症反应的介导因子尚未明确。本研究发现，高迁移率族蛋白B1（high-mobility group box 1, HMGB1）——一种损伤相关分子模式（damage-associated molecular pattern）——可由铜死亡细胞释放，从而启动炎症反应。从机制层面分析，铜蓄积引发的三磷酸腺苷（adenosine triphosphate, ATP）耗竭会激活腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK），进而促进HMGB1的磷酸化，最终使其胞外释放量增加。与之相反，通过基因手段（采用RNA干扰，RNAi）或药理学手段（采用多索莫芬（dorsomorphin））抑制AMPK激活，可抑制铜死亡进程并减少HMGB1的释放。功能实验表明，缺失HMGB1的铜死亡细胞促进晚期糖基化终末产物特异性受体（advanced glycosylation end product-specific receptor, AGER，亦称RAGE）依赖性炎症细胞因子生成的能力显著减弱。综上，HMGB1是铜死亡引发无菌性炎症的关键免疫介导因子。