Review of preclinical interventions for heat stroke pathophysiology and gaps

Heat stroke (HS) is a life-threatening acute condition characterized by hyperthermia, central nervous system dysfunction, and multiple organ failure. Energy metabolism disruption serves as a pivotal link between hyperthermia and multi-organ injury. This review synthesizes current evidence on the mechanisms of energy metabolism dysregulation in HS and evaluates emerging intervention strategies. Mitochondrial dysfunction—manifested as structural damage, oxidative phosphorylation impairment, and excessive fission—represents an initiating event. This is followed by glucose-lipid metabolic restructuring, impaired substrate utilization, and energy depletion. These metabolic derangements mediate secondary injury in the intestine (barrier disruption and endotoxemia), brain (hypothalamic dysregulation), and lung (oxidative stress and barrier leakage). Intervention strategies are categorized into mitochondrial protection (e.g., astragaloside IV, curcumin), mitophagy modulation (e.g., melatonin, rapamycin), and substrate metabolism regulation (e.g., taurine, acetyl-L-carnitine). Notably, most current evidence for these interventions is derived from preclinical studies, and HS-validated human studies are still needed to confirm their efficacy and safety. While these approaches show promise in preclinical models, translational gaps remain, including limited validation in HS-specific models, lack of biomarker-guided patient stratification, and insufficient data on vulnerable populations. Future priorities include dynamic metabolic monitoring, identification of early-warning biomarkers, and development of personalized interventions tailored to age, comorbidity status, and metabolic phenotype.