Fan_2026_Front.Physiol_17_1821632

High-altitude environments impose substantial metabolic constraints on human physiology, with oxygen limitation driving profound alterations in lipid regulation. This narrative review synthesizes current evidence on the context-dependent effects of high-altitude hypoxia (HAH) on systemic lipid metabolism across high-altitude native populations and lowlanders exposed to altitude, with particular attention to Tibetan and Andean settings. Acute hypoxic exposure is characterized by rapid lipid mobilization, enhanced glycolytic flux, suppressed lipoprotein lipase activity, and dynamic fluctuations in circulating lipids. In contrast, acclimatization and long-term adaptation are associated with a shift toward more oxygen-efficient substrate utilization, often accompanied by reduced fatty-acid oxidation, improved insulin sensitivity, and population-specific changes in lipid profiles. However, in non-acclimatized or metabolically vulnerable individuals, sustained HAH exposure may also promote dyslipidemia, inflammation, and adverse cardiometabolic effects. By integrating evidence on HIF-mediated metabolic reprogramming, neuroendocrine regulation, genetic adaptation, and the microbiota-bile acid axis, this review highlights the heterogeneity of lipid responses to hypoxia and discusses their implications for cardiometabolic risk, preventive medicine, and future altitude-related metabolic research.