ZBP1 at the Interface of Nucleic-Acid Stress and Inflammatory Cell Death After Intracerebral Hemorrhage: A Hypothesis-Driven Overview.

Intracerebral hemorrhage (ICH) creates a sterile perihematomal niche in which erythrocyte lysis, heme and iron toxicity, mitochondrial damage, blood-brain barrier disruption and innate immune activation converge. Which nucleic-acid sensors translate this biochemical stress into inflammatory cell death remains unresolved. Z-DNA-binding protein 1 (ZBP1) can recognize Z-conformation nucleic acids and couple ligand sensing to RIPK1, RIPK3, MLKL, caspase-8 and inflammasome-associated modules. We performed a targeted, evidence-graded narrative search, updated on 29 August 2026, to ask four questions: which components of the proposed pathway are established in ICH, which are transferable from other systems, which remain hypothetical, and what findings would falsify or validate the model? ICH studies demonstrate cytosolic mitochondrial DNA release and increasingly support cGAS-STING and AIM2 activation, while genetic and biochemical studies establish RIPK1-RIPK3-MLKL-dependent necroptotic signaling. However, Z-conformation ligands, ZBP1 ligand binding, ZBP1-containing complex assembly and ZBP1-dependent injury have not been demonstrated in ICH. The two ICH reports involving ZBP1 provide transcriptomic or intervention-associated observations rather than dependency evidence. Human and murine ZBP1 also differ in RIPK1/RIPK3 and RHIM requirements, limiting direct translation from mouse genetics. We therefore frame ZBP1 as a falsifiable candidate mechanism, not an established target, and define validation criteria based on cell-type-specific loss of function, ligand capture, complex formation, pathway epistasis, functional rescue and preservation of hematoma clearance.