Background and Significance: The prevalence of metabolic syndrome (MetS), characterized by a cluster of metabolic abnormalities including obesity, hypertension, dyslipidemia, and hyperglycemia, poses a significant global health challenge. Recent research has highlighted the potential therapeutic benefits of chronic intermittent hypobaric hypoxia (CIHH), a condition simulating high-altitude exposure, in ameliorating MetS symptoms. While studies on CIHH in MetS models have shown promising results, its effects on healthy individuals as controls remain largely unexplored. Given the central role of the liver in regulating metabolic processes, a deeper understanding of the molecular mechanisms underlying CIHH's differential effects on healthy and MetS mice is crucial for developing targeted interventions. Objectives: The primary objective of this project is to conduct a comprehensive comparative analysis of the effects of CIHH on liver tissues from both healthy and MetS mice, utilizing proteomic approaches. The specific aims are: 1.To establish and validate a mouse model of MetS through a high-fat diet and fructose water feeding regimen. 2.To investigate the differential effects of CIHH on liver proteomes in healthy and MetS mice. 3.To identify key proteins and signaling pathways involved in CIHH's alleviation of MetS symptoms, particularly focusing on the hypoxia-inducible factor (HIF)-1 signaling pathway. 4.To elucidate the underlying molecular mechanisms through which CIHH exerts its beneficial effects on MetS, while minimizing potential adverse effects on healthy individuals. Methods: Animal Models and Grouping: Male C57BL/6J mice will be randomly assigned to four groups: control (CON, healthy mice), CIHH (healthy mice exposed to CIHH), MetS (mice with induced MetS), and MetS+CIHH (MetS mice exposed to CIHH). MetS Model Induction: Mice in the MetS and MetS+CIHH groups will undergo a 16-week regimen of a high-fat diet and 10% fructose water consumption to induce MetS symptoms. CIHH Treatment: Following the establishment of the MetS model, mice in the CIHH and MetS+CIHH groups will be subjected to CIHH conditions, simulating an altitude of 5000 meters for 6 hours daily over 28 days. Assessment and Analysis: 1.Metabolic Syndrome Indicators: Routine measurements of diagnostic criteria for MetS, including body weight, blood pressure, fasting blood glucose, insulin levels, and lipid profiles, will be performed. 2.Western Blotting: Expression levels of proteins related to the HIF-1 signaling pathway in liver tissues will be assayed to assess changes in this critical pathway. 3.Quantitative Proteomic Analysis: Liver tissues from all groups will undergo quantitative proteomic analysis using mass spectrometry. This will enable the identification of differentially expressed proteins and their associated pathways, providing insights into the molecular mechanisms of CIHH's effects. Expected Outcomes: This project anticipates the identification of specific proteins and signaling pathways that are differentially regulated by CIHH in healthy and MetS mice. By elucidating the mechanisms underlying CIHH's alleviation of MetS symptoms, we aim to contribute to the development of novel therapeutic strategies for MetS management. Furthermore, the study's findings on CIHH's effects on healthy mice will inform the safety and applicability of this intervention in the general population. Conclusion: In conclusion, this project represents a critical step towards understanding the complex interplay between CIHH and metabolic health. By leveraging advanced proteomic technologies, we aim to unravel the molecular underpinnings of CIHH's differential effects on healthy and MetS mice, ultimately advancing our knowledge of MetS pathogenesis and treatment options.