NMN通过抑制小胶质细胞铁下垂来减轻高原缺氧引起的认知障碍
NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis.
摘要(中文译文)
铁死亡是一种与缺氧密切相关的铁依赖性程序性细胞死亡形式。暴露于高原缺氧环境会诱导大脑发生铁死亡，同时过度激活小胶质细胞并增强其吞噬活性，最终导致神经毒性和记忆丧失。NMN是一种强效的NAD前体补充剂。补充NMN可提高体内NAD水平，从而减轻长期暴露于高原低压缺氧环境所造成的损伤。尽管NMN在改善高原缺氧诱导的小胶质细胞铁死亡方面显示出治疗潜力，但其具体调控机制仍不清楚。我们通过体内和体外模型实验研究了NMN调控缺氧诱导的小胶质细胞铁死亡的生物学机制。我们的研究结果揭示，高原缺氧加剧了小胶质细胞铁死亡，而外源性添加NMN可改善铁死亡。此外，基因调控技术证实，沉默Sirt1削弱了NMN的神经保护作用，同时加剧了缺氧诱导的氧化损伤。在机制上，NMN给药增强了NAD/NADH循环，激活了Sirt1/Nrf2/HO-1通路并减弱了HIF-1α积累，从而增强GSH/GPX4轴的抗氧化功能，进而最大限度地减少高原缺氧诱导的小胶质细胞铁死亡，最终有益于认知功能。NMN的使用增强了NAD前体的临床应用潜力，并为开发有效靶向神经系统疾病中铁死亡的治疗方法提供了有前景的策略。
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.
如何引用
AMA
Longfei Xu, Zilin Wei, Aili Wei, Kun Wang, Tianhui Wang. NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.153967.
APA
Longfei Xu, Zilin Wei, Aili Wei, Kun Wang, Tianhui Wang (2026). NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.153967
GB/T 7714
Longfei Xu, Zilin Wei, Aili Wei, Kun Wang, Tianhui Wang. NMN mitigates high-altitude hypoxia-induced cognitive impairment by inhibiting microglial ferroptosis.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.153967.
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