HMGB1 is a mediator of cuproptosis-related sterile inflammation

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.

Automated summary

This study found that cuproptotic cells release HMGB1 to initiate inflammation. Mechanistically, copper accumulation-induced ATP depletion activates AMPK to promote HMGB1 phosphorylation, resulting in increased release. Inhibiting AMPK activation reduces cuproptosis and HMGB1 release. Cuproptotic cells deficient in HMGB1 show reduced production of inflammatory cytokines. Thus, HMGB1 is a key mediator of sterile inflammation initiated by cuproptosis.