A New Paradigm for Precision Medicine in Heatstroke: From Molecular Subtyping to Targeted Prevention and Treatment.

Heatstroke is a life-threatening systemic disorder caused by extreme heat exposure and characterized by thermal toxicity, dysregulated inflammation, endothelial injury, and coagulation abnormalities. Despite timely cooling and supportive care, marked inter-individual heterogeneity in disease onset, dominant pathological processes, and outcomes remains a major barrier to early recognition and effective intervention. Increasing evidence indicates that heatstroke represents a spectrum of mechanistically distinct subtypes rather than a uniform clinical entity. This review summarizes advances relevant to a precision medicine framework for heatstroke. We examine candidate genetic factors associated with susceptibility, including rare variants with potentially large effects on calcium homeostasis and thermosensing, as well as common polymorphisms that may influence inflammatory, endothelial, and coagulation responses. We propose a conceptual molecular classification centered on three interconnected pathological axes: inflammation-dominant, endothelial injury-dominant, and coagulation-dominant phenotypes, with dynamic overlap during disease progression. Emerging multi-omics approaches, including genomics, transcriptomics, proteomics, metabolomics, and single-cell profiling, are discussed as potential tools for biomarker discovery, subtype stratification, and prognostic assessment. However, most remain investigational, and their clinical utility, generalizability, and feasibility across different healthcare settings require prospective validation before routine implementation. We also discuss host-microbe sequencing for distinguishing infection from sterile inflammation and a proteomic model for identifying heatstroke-induced coagulopathy. Precision medicine provides a promising framework for heatstroke research and management. If prospectively validated, this framework may complement standard care by integrating molecular phenotypes with clinical and environmental factors to improve risk prediction, diagnosis, and mechanism-guided interventions, particularly in high-risk populations facing escalating heat exposure.