Molecular Mechanisms of Heatstroke: Pathophysiology and Cell Death Pathways

Heatstroke is a severe, life-threatening condition characterized by a core body temperature exceeding 40°C, accompanied by central nervous system dysfunction such as confusion, seizures, or coma. It often presents with systemic inflammation and multi-organ failure, including injury to the liver, kidneys, brain, and coagulation system. The molecular pathogenesis of heatstroke is multifactorial, involving a cascade of intracellular and extracellular events triggered by excessive heat. These include protein denaturation, loss of cellular homeostasis, oxidative stress, mitochondrial dysfunction, and the release of damage-associated molecular patterns (DAMPs) that activate immune responses. In parallel, regulated cell death pathways such as apoptosis, necroptosis, pyroptosis, and ferroptosis are initiated, amplifying tissue injury. Key molecular mediators include heat shock proteins, proinflammatory cytokines, and reactive oxygen species. This review summarizes current understanding of the molecular and cellular mechanisms underlying heatstroke, highlighting potential biomarkers and therapeutic targets that may improve diagnosis, prognostication, and clinical management of this increasingly relevant condition.