DNA methylation regulation of CYP450-lipid metabolism by high-altitude hypoxia: linking neuroinflammation to cognitive impairment

Abstract Under high-altitude hypoxia, neuroinflammation contributes to cognitive impairment, though the underlying mechanisms remain unclear. In this study, we established rat and astrocyte models of hypoxic exposure. We found that hypoxia induced significant alterations in blood biochemistry, widespread neuronal and glial damage, and impaired spatial learning and memory in rats, which were associated with the abnormal accumulation of p-Tau and Aβ. Hypoxia also triggered neuroinflammation, increasing the levels of inflammatory mediators and activating microglia and astrocytes. Targeted metabolomics and molecular analyses revealed disrupted oxidized lipid metabolism, including reduced synthesis of key metabolites such as arachidonic acid derivatives, accompanied by downregulation of cytochrome P450 (CYP450) expression. In vitro, hypoxia enhanced astrocyte inflammation, promoted Aβ/p-Tau accumulation, increased apoptosis, and suppressed CYP450. Inhibition of CYP450 (particularly epoxygenase) exacerbates hypoxia-induced inflammatory responses and promotes abnormal accumulation of cognition-related proteins by negatively regulating the NF-κB inflammatory signaling pathway. Furthermore, CYP450 downregulation was associated with DNA methylation changes. These findings highlight the role of DNA methylation-mediated CYP450 and oxidative lipid metabolic dysregulation in hypoxia-induced neuroinflammation and cognitive deficits, offering new insights for the development of neuroprotective strategies targeting the CYP450-oxidized lipid axis.