Liurong Lin,1,2,* Xin Ling,1,2,* Ting Chen,1,2,* Qian Zhou,1,2 Jinghao Huang,1,2 Linshen Huang,1,2 Xianzhong Lin,1,2 Lanying Lin1,2 

1Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, People’s Republic of China; 2Department of Anesthesiology, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xianzhong Lin; Lanying Lin, Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian, 350005, People’s Republic of China, Email linlanying@163.com

Background: Perioperative neurocognitive disorders (PND) are common in elderly patients after surgery, leading to long-term cognitive decline and reduced quality of life. The mechanisms are unclear, but ferroptosis, a key cell death pathway, may be involved in the disruption of brain homeostasis during perioperative stress.
Methods: In this study, we used the SAM-P8 mouse model to simulate brain aging and observe isoflurane-induced ferroptosis. Forty 8-month-old SAM-P8 mice were divided into four groups: control (CON), perioperative cognitive dysfunction (PND), PND with Liproxstatin-1 intervention (PND+Lip-1), and Liproxstatin-1 control (Lip-1). After 3% isoflurane anesthesia in the PND group, the PND+Lip-1 group received daily intrathecal Liproxstatin-1 injections for five days. Behavioral tests assessed spatial learning and memory. Nissl staining, transmission electron microscopy (TEM), FJB (Fluoro-Jade B), Western Blot (WB), and enzyme-linked immunosorbent assay (ELISA) evaluated neuronal morphology and levels of iron metabolism and lipid peroxidation markers.
Results: Behavioral tests indicated a decline in learning and memory function in the PND mice. Liproxstatin-1 treatment improved cognitive performance, restored normal neuron ratios, and alleviated mitochondrial damage. In the PND group, increased Cluster of Differentiation 71 (CD71) and decreased Ferroportin 1 (FPN1) and Glutathione Peroxidase 4 (GPx4) indicated ferroptosis activation, while Liproxstatin-1 normalized these markers, reduced ferrous ion concentration, Malondialdehyde (MDA), Reactive Oxygen Species (ROS), and 4-Hydroxy-2-nonenal (4-HNE) levels, and decreased Interleukin-6 (IL-6), showing anti-inflammatory effects.
Conclusion: The results of this study suggest that isoflurane-induced ferroptosis may play an important role in the pathologic progression of PND. The application of liproxstatin-1, a lipid peroxidation inhibitor, provides a new potential therapeutic target for perioperative neuroprotection.

Keywords: perioperative neurocognitive disorder, isoflurane, ferroptosis, lipid peroxidation, neuroprotection, SAM-P8 mice