Integrated proteomic and metabolomic analyses define the molecular architecture of acute mountain sickness.

BACKGROUND: Hypoxia-driven vascular, immune, and metabolic remodeling is a key biological process involved in cardiovascular diseases, cancer, and other complex systemic disorders. Acute mountain sickness (AMS) is an acute manifestation of hypobaric hypoxia, but its systemic molecular features remain incompletely defined. METHODS: We performed integrated plasma proteomic and metabolomic profiling in 81 healthy Han Chinese male participants after rapid high-altitude exposure. Differential analysis, weighted gene co-expression network analysis (WGCNA), tissue-specific protein mapping, regulatory network reconstruction, machine learning, and druggability assessment were applied to characterize AMS-associated molecular alterations and identify candidate biomarkers and targets. RESULTS: Multi-omics profiling identified 3,137 proteins and 4,104 metabolites and showed clear separation between AMS and non-AMS participants. AMS was characterized by coordinated thrombo-inflammatory activation, coagulation-related disturbance, and metabolic reprogramming, including suppression of oxidative phosphorylation-related signatures. WGCNA identified symptom associated proteomic and metabolomic modules linked to headache severity, oxygen saturation, and hemodynamic traits. Tissue-specific protein mapping revealed a liver-centered but multi-organ circulating proteomic architecture, suggesting hepatic secretory remodeling with additional neural and immune-system contributions. Regulatory network analysis highlighted NOTCH1 as a candidate upstream regulatory hub, whereas druggability analysis prioritized NOTCH1 and the antioxidant-related protein GSTA1 as translational candidates. An mRMR plus logistic regression classifier integrating 15 proteomic features and SpO2 achieved good discriminatory performance, with an AUC of 0.968 in the training cohort and 0.913 in the test cohort. CONCLUSION: This study defines a multi-layer molecular framework of human acute hypoxic stress, linking vascular regulation, inflammation, coagulation, metabolic remodeling, tissue origin, and biomarker prioritization. These findings provide mechanistic insight into AMS and support multi-omics-based biomarker discovery and target prioritization in hypoxia-associated systemic diseases.