Liproxstatin‐1 alleviates ferroptosis in sevoflurane anesthesia‐induced cognitive deficits of aged mice: The role oxidative stress

Abstract In this study, we aimed to validate the hypothesis that the interplay between sevoflurane, oxidative stress and ferroptosis is crucial for the pathogenesis of sevoflurane‐induced cognitive impairment in aged individuals. The mice with sevoflurane‐induced cognitive impairment were used to explore the effects of sevoflurane on oxidative stress, iron homeostasis, and cognitive function in aged mice. Iron content and oxidative stress markers were analyzed in hippocampal tissue homogenates using specific assays. Additionally, the levels of iron death‐related markers (Fth1 and Gpx4) were assessed by real‐time PCR and Western blotting. Morris Water Maze and novel object recognition (NOR) tests were conducted to evaluate cognitive function. Sevoflurane exposure in aged mice resulted in a significant increase in iron overloading in the hippocampus, followed by a subsequent stabilization. Oxidative stress levels were elevated in the hippocampal tissue of sevoflurane‐exposed mice, and a significant correlation was observed between iron death and oxidative stress. Liproxstatin‐1, a ferroptosis inhibitor, effectively ameliorated the decline in memory and learning abilities induced by sevoflurane anesthesia. Liproxstatin‐1 treatment reduced iron overload and oxidative stress in the hippocampal tissue of aged mice. The expression of Fth1 and Gpx4, iron death‐related markers, was downregulated following Liproxstatin‐1 intervention. Our findings suggest that sevoflurane anesthesia disrupts iron homeostasis, leading to increased oxidative stress and cognitive impairment in aged mice. These results highlight the potential of targeting iron‐mediated processes to mitigate sevoflurane‐induced cognitive impairment in the aging population.