補体-凝固カスケードと代謝調節不全が軽度から重度の熱中症への移行を支える：臨床およびプロテオミクスを組み合わせた研究

Heat stroke (HS) is a life-threatening condition marked by hyperthermia, central nervous system dysfunction, and multi-organ injury. Exertional heatstroke (EHS), which commonly affects healthy young people, typically follows intensity training or heavy physical labor in high temperature and high humidity environment. However, the molecular events driving the progression from mild to severe EHS remain poorly understood. This study integrated clinical data with serum proteomics to identify key pathways and biomarkers involved in EHS progression.

From June 2022 to October 2023, serum samples were collected from heat stroke, including 7 mild and 7 severe cases, with the remaining as controls. Demographic data, laboratory results, and Sequential Organ Failure Assessment (SOFA) scores were recorded. Serum proteins were analyzed using label-free mass spectrometry. Differentially expressed proteins (DEPs) were identified and analyzed using protein-protein interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Comparisons between mild vs. control, severe vs. control, and severe vs. mild groups were performed with Benjamini-Hochberg correction. Receiver operating characteristic analysis was used to evaluate discriminative ability; proteins with area under the curve (AUC) ≥0.85 and a lower bound of the 95% confidence interval ≥0.50 were selected. ELISA was used for further validation.

Compared with patients with mild EHS, patients with severe EHS exhibited significantly higher markers of inflammation (WBC), coagulation abnormalities (PT, APTT, fibrinogen, D-dimer), organ injury (CK-MB, AST, LD, Creatinine, Uric Acid), and higher SOFA scores (P < 0.05). Proteomic profiling identified 51 shared DEPs across comparisons. PPI analysis highlighted proteins in the complement and coagulation cascades. Enrichment results indicated significant activation of complement-coagulation pathways, nuclear factor kappa-B (NF-κB) signaling, metabolic dysregulation, and immune responses. Key biomarkers-such as von Willebrand factor (vWF), mannose-binding lectin serine protease 1 (MASP1), coagulation factor VIII (F8), and protein C (PROC)-demonstrated strong discriminative performance and were associated with disease severity. Meanwhile, serum levels of HSPA13 (HSP70) and HSP90AA1/HSP90B1 (HSP90) were elevated in both mild and severe EHS relative to controls, with no significant differences between severity groups.

Complement-coagulation activation and metabolic dysregulation appear to drive the transition from mild to severe EHS. The proteins MASP-1, F8, PROC, and vWF represent promising biomarkers and potential therapeutic targets. These findings offer mechanistic insights for early risk stratification and targeted intervention in EHS.