Near-infrared light improves postoperative cognitive dysfunction by alleviating Lcn2-dependent ferroptosis induced...

Iron overload and oxidative stress significantly contribute to the pathophysiology of postoperative cognitive dysfunction (POCD). Our previous findings demonstrated that transcranial near-infrared (NIR) light alleviates POCD by reducing oxidative stress; however, the underlying mechanism remains unclear. This study aimed to investigate whether NIR light ameliorates ferroptosis following POCD and to identify potential regulatory factors involved in this process.

POCD model mice were treated with NIR light, followed by behavioral testing to assess their cognitive performance. Ferroptosis was evaluated through measurements of iron concentrations; reactive oxygen species (ROS) levels; and the concentrations of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and glutathione (GSH). Lipocalin 2 (Lcn2) was examined as a potential mediator of NIR-regulated ferroptosis. HT22 hippocampal neurons were subjected to NIR irradiation and cotreated with the ferroptosis inhibitor ferrostatin-1 (Fer-1) and a small interfering RNA (siRNA) targeting Lcn2. Additionally, POCD mice received intrahippocampal injections of recombinant (RE) Lcn2 protein, to explore the role of Lcn2 in improving POCD via NIR.

NIR light improved cognitive function, suppressed ferroptosis, and preserved neuronal integrity in POCD mice. The upregulation of Lcn2 following POCD was attenuated by NIR treatment. NIR light alleviated glutamate (Glu)-induced ferroptosis in HT22 cells in vitro through the modulation of Lcn2. Notably, Lcn2 overexpression suppressed the therapeutic effects of NIR light in POCD mice.

Lcn2 mediates neuronal ferroptosis in the context of POCD, and this pathway can be inhibited by NIR light therapy.