Heat stress activates the coagulation cascade through Z-DNA-binding protein 1-dependent necroptosis.

Heatstroke, a severe hyperthermic condition, is characterized by a core body temperature >40°C and multiple organ dysfunction syndrome (MODS), with an extremely high mortality rate. Despite advances in identifying heatstroke-induced cell death pathways, the molecular cascades that bridge heat-induced cell death to MODS and mortality are not yet fully characterized. Our findings demonstrate that Z-DNA-binding protein 1 (ZBP1)-triggered disseminated intravascular coagulation critically drives MODS and fatal outcomes in heatstroke. Heat stress activates ZBP1-dependent necroptosis, promoting tissue factor (TF) release and phosphatidylserine (PS) externalization. Genetic knockout of ZBP1 or its downstream necroptotic effectors, reduction of global TF expression, suppression of PS exposure, or pharmacological inhibition of the coagulation cascade attenuates heat stress-induced coagulation activation, organ injury, and death. Comparable results are obtained in heat-stressed mice with conditional knockout of ZBP1 in hematopoietic or myeloid lineages. Overall, our study reveals the critical role of ZBP1-mediated necroptosis in bridging heat stress and coagulation dysfunction.