NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis

Ferroptosis is a form of iron-dependent programmed cell death closely associated with hypoxia. Exposure to high-altitude hypoxic environments induces ferroptosis in the brain while simultaneously hyperactivating microglia and enhancing their phagocytic activity, ultimately leading to neurotoxicity and memory loss. NMN is a potent NAD⁺ precursor supplement. Supplementing with NMN elevates NAD⁺ levels in the body to mitigate damage caused by prolonged exposure to high-altitude hypobaric hypoxia environments. Although NMN shows therapeutic potential in ameliorating microglial ferroptosis induced by high-altitude hypoxia, its specific regulatory mechanisms remain unclear. We investigated the biological mechanisms by which NMN regulates hypoxia-induced microglial ferroptosis through in vivo and in vitro model experiments. Our findings reveal that high-altitude hypoxia exacerbates ferroptosis in microglia, while exogenous addition of NMN ameliorates ferroptosis. Furthermore, gene regulation technique confirmed that silencing Sirt1 weakened NMN's neuroprotective effects while exacerbating hypoxia-induced oxidative damage. Mechanistically, NMN administration enhances the NAD⁺/NADH cycle, activates the Sirt1/Nrf2/HO-1 pathway and attenuates HIF-1α accumulation to enhance antioxidant function of GSH/GPX4 axis, thereby minimizing microglial ferroptosis induced by high-altitude hypoxia, ultimately benefiting cognitive function. The use of NMN enhances the clinical application potential of NAD⁺ precursors and offers a promising strategy for developing therapeutic approaches that effectively target ferroptosis in neurological diseases.