Phenotypic study on human high-altitude acclimatization

High-altitude acclimatization is a compensatory process, through which the human body adapts to high-altitude environments. Such environments are characterized by hypobaric hypoxia, low temperatures and intense UV radiation. High-altitude acclimatization is very heterogenous. Between 10%–85% of travelers to high altitude may experience symptoms of acute high-altitude illness. Traditional research, often constrained by limited sample sizes, single-system focus and fragmented study periods, has been insufficient to elucidate the coordinated, cross-system mechanisms underlying acclimatization. Phenomics, through the integration of multi-scale phenotypes and multi-omics data, offers a novel approach for deciphering these mechanisms. This study systematically reviews recent advances in the phenomics of high-altitude acclimatization. (i) Cohort development: international studies (e.g., Operation Everest II, AltitudeOmics) have provided initial explorations of physiological responses to altitude. The team of Fudan University established a comprehensive longitudinal cohort of over 1000 individuals, collecting 16 categories of phenotypes ranging from macroscopic physiological parameters to microscopic omics. This enabled the mapping of the dynamic trajectory of acclimatization. (ii) Methodological innovations: the composite phenotype analysis (CPA) algorithm integrated 33 physiological indicators, identifying 9 functional modules (e.g., circulation, hematopoiesis). This revealed synergistic regulation between the circulatory system and immune/renal function during the acute phase of high-altitude acclimatization. Multi-omics technologies identified new genes (e.g., EPAS1, EGLN1) regulating oxygen metabolism via the HIF pathway. Notably, variants of EPAS1 are common in Tibetans and reduce the risk of high-altitude illness via reducing hemoglobin concentration. (iii) New intervention strategies: light intervention can stabilize circadian rhythms and enhance cardiac hypoxia tolerance. Moderate-intensity pre-acclimatization can improve oxygen transport capacity. Pharmacological interventions (e.g., acetazolamide, the Tibetan herbal medicine Wuweiganlu) and targeted therapies (e.g., modulating erythropoiesis via the SNX4 gene) demonstrate therapeutic potential in both acute and chronic mountain sickness. Despite these advances, challenges remain. Our cohort represents a limited part of the population; the mechanisms of the acclimatization processes are still incompletely resolved; and targeted therapies are still in early developmental stages. Future research needs to establish ultra-large-scale, multi-ethnic cohorts, integrating spatiotemporal multi-omics and organoid models, to build a “genetic typing-multimodal prediction-precision-intervention” framework. This will enable proactive prevention and control in high-altitude medicine.