Zhang Da-Wei, Yang Ming-Ming, Zhou Meng-Xi, Wei Yuan-Yuan, Hu Lei, Hong Mei, Chen Ting-Ting, Wang Xiao-Min, Ding Yi-Chuan, Wei Chuan-Sheng, Li Fang, Chen Wen, Kang Jia-Ying, Ye Jing-Jing, Fei Guang-He
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China; Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, 230022, Anhui Province, People's Republic of China.
Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China.
Redox Biol. 2025 May 13;85:103673. doi: 10.1016/j.redox.2025.103673.
Cognitive dysfunction is an essential comorbidity that contributing to the whole disease process of the individual of chronic obstructive pulmonary disease (COPD), yet its specific mechanism remains controversial due to a lack of cellular and molecular evidence. Our clinical data revealed a significant reduction in total hippocampal volume in patients with COPD, with the CA1 subfield notably smaller and associated with lung function. Long-term CS exposure caused hippocampus impairment, leading to spatial and working memory impairments in COPD model mice. CS exposure triggered ferroptosis in vivo and in vitro. Bioinformatics analysis suggested that sestrin2 is a key ferroptosis-related gene involved in cognitive impairment. Sestrin2 protein levels were consistently increased in the hippocampus of COPD model mice and CSE treated HT22 cells. Sestrin2 knockdown exacerbated ferroptosis and enhanced the down-regulation of synaptophysin and PSD95, while sestrin2 overexpression inhibited these damaging processes in vitro. This neuroprotection of sestrin2 is dependent on its binding with heterogeneous nuclear ribonucleoprotein L (HNRNPL). Moreover, sestrin2 overexpression and DFO ameliorated hippocampal impairment and neurocognitive deficits by correcting CS-induced ferroptosis and synaptic proteins alterations in vivo. Overall, our study reveals that sestrin2 improves CS-induced adverse changes in hippocampal neurons and neurobehavior, providing new insights into the molecular mechanisms underlying COPD-related cognitive dysfunction.
认知功能障碍是慢性阻塞性肺疾病（COPD）患者个体整个疾病过程中的一种重要合并症，但其具体机制因缺乏细胞和分子证据仍存在争议。我们的临床数据显示，COPD患者海马总体积显著减少，其中CA1亚区明显更小且与肺功能相关。长期接触香烟烟雾（CS）导致COPD模型小鼠海马损伤，进而导致空间和工作记忆障碍。CS暴露在体内和体外均引发铁死亡。生物信息学分析表明， sestrin2是参与认知障碍的关键铁死亡相关基因。在COPD模型小鼠海马和经香烟烟雾提取物（CSE）处理的HT22细胞中，Sestrin2蛋白水平持续升高。敲低Sestrin2会加剧铁死亡，并增强突触素和突触后致密蛋白95（PSD95）的下调，而Sestrin2过表达在体外可抑制这些损伤过程。Sestrin2的这种神经保护作用依赖于其与不均一核核糖核蛋白L（HNRNPL）的结合。此外，Sestrin2过表达和去铁胺（DFO）通过纠正体内CS诱导的铁死亡和突触蛋白改变，改善了海马损伤和神经认知缺陷。总体而言，我们的研究表明，Sestrin2改善了CS诱导的海马神经元和神经行为的不良变化，为COPD相关认知功能障碍的分子机制提供了新的见解。
