Study on the role and mechanism of CIH-activated ferroptosis in secondary cognitive impairment due to OSAHS

Abstract

Objective This study investigates whether chronic intermittent hypoxia (CIH) induces cognitive deficits through IL-6/hepcidin-mediated ferroptosis in patients and animal models with obstructive sleep apnea-hypopnea syndrome (OSAHS). Clinical and animal research demonstrates that activation of this signaling axis triggers hippocampal ferroptosis and subsequent cognitive dysfunction. The features of sleep EEG alongside this molecular mechanism present novel targets for early diagnosis and intervention strategies. Methods This study enrolled 99 patients with OSAHS, classified into healthy controls (n = 25), mild-to-moderate (n = 25), and severe OSAHS (n = 49) groups based on polysomnography. Clinical assessments included neuropsychological tests, EEG spectral analysis, and ferroptosis-related biomarkers. A chronic intermittent hypoxia (CIH) rat model was established to evaluate cognitive function and ferroptosis-related alterations. The IL-6/hepcidin axis was further investigated in CIH rats and BV2 microglial cells using IL-6 or its inhibitor GSHP. Results Studies have demonstrated that respiratory incidents during sleep and changes in molecules associated with ferroptosis play a role in cognitive and emotional impairments in individuals suffering from OSAHS. Research involving animal models suggests that CIH induces ferroptosis within the hippocampus, leading to declines in cognitive function. Hippocampal ferroptosis was evidenced by reduced expression of GPX4 and FTH1, increased ACSL4 levels, elevated malondialdehyde (MDA) and lipid peroxide (LPO) content, and enhanced ROS fluorescence, consistent with iron-dependent lipid peroxidation and impaired antioxidant defense. This process is modulated by the IL-6/hepcidin pathway, the activation of which increases iron accumulation and lipid peroxidation, while inhibiting this pathway can mitigate the resultant damage. Conclusion Patients diagnosed with OSAHS often experience cognitive and emotional disturbances associated with sleep-related respiratory disorders. Our findings suggest that persistent intermittent hypoxia activates the IL-6/hepcidin pathway, triggers ferroptosis, and ultimately leads to hippocampal neuronal damage and cognitive decline in patients with OSAHS. Monitoring sleep parameters facilitates early diagnosis, while interventions targeting ferroptosis and related pathways may represent promising therapeutic approaches.