Histopathological and molecular mechanisms of multi-organ damage in heat stroke: Endothelial failure, immune crosstalk, and regulated cell death pathways.

Abstract

Heat stroke is a life-threatening condition characterized by severe hyperthermia accompanied by central nervous system dysfunction and progressive multi-organ injury. Although rapid cooling remains the cornerstone of clinical management, accumulating evidence indicates that normalization of core body temperature alone does not fully prevent delayed organ damage. Experimental and clinical studies increasingly demonstrate that heat stroke-induced pathology extends beyond acute thermal injury and involves sustained endothelial dysfunction, coagulation imbalance, sterile inflammation, mitochondrial failure, and regulated cell death pathways. Histopathological analyses across multiple organs, including the brain, liver, kidneys, and intestine, reveal persistent microvascular injury, tissue edema, microthrombi formation, inflammatory infiltration, and cellular degeneration following the hyperthermic phase. These tissue-level alterations are closely linked to molecular mechanisms such as endothelial glycocalyx disruption, inflammasome activation, mitochondrial dysfunction, and dysregulated immune-coagulation crosstalk. Importantly, these interconnected processes form a self-amplifying injury network that contributes to delayed neurological deterioration and systemic organ failure despite effective cooling. This review integrates histopathological and molecular evidence from experimental models and human studies to provide a systems-level framework of post-hyperthermic injury in heat stroke. By linking tissue pathology with underlying mechanisms and translational therapeutic targets, this article highlights why cooling alone is insufficient and emphasizes the need for multimodal, mechanism-based interventions to mitigate delayed organ injury and improve clinical outcomes.