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

Abstract

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.

Key Findings

• High-altitude hypoxia exacerbates ferroptosis in microglia, leading to neurotoxicity and cognitive impairment.
• NMN supplementation elevates NAD+ levels, activates the Sirt1/Nrf2/HO-1 pathway, and enhances antioxidant defenses via the GSH/GPX4 axis, thereby reducing microglial ferroptosis.
• Silencing Sirt1 weakens NMN's neuroprotective effects and worsens hypoxia-induced oxidative damage.

Clinical Significance

Citation

Xu Longfei, Wei Zilin, Wei Ailiet al.. NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis. Biochemical and biophysical research communications. 2026-May-15.