Sestrin2 alleviates cognitive impairment via inhibiting hippocampus ferroptosis in cigarette smoke-induced chronic obstructive pulmonary disease.

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.