The globular domain of extracellular histones mediates cytotoxicity via membrane disruption mechanism.

Histones are traditionally recognized for structuring nuclear architecture and regulating gene expression. Recent advances have revealed their roles in inflammation, coagulation, and immune responses, where they act as damage-associated molecular patterns. The mechanisms by which histones induce membrane leakage are not well understood, and certain cells, including endothelial cells and peritoneal macrophages, show resistance to histone-mediated pore formation. We utilized liposome leakage assays to explore the pore-forming capabilities of different histone configurations, including individual histones, tail regions, and globular domains. Our results demonstrate that globular domains primarily drive pore formation. Using cytotoxicity assays, we further demonstrate that the globular domain of extracellular histones is primarily implicated in inducing lytic cell death. This study provides insights into the pathological roles of histones and suggests potential therapeutic targets to mitigate their harmful effects.