Background and aim Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in rats with MS. Methods Male Sprague-Dawley rats aged 8–10 weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at simulated altitude of 5000 meters for 28 days, 6 hours daily), MS model (induced by 16-week high fat diet and 10% fructose water feeding) and MS + CIHH (exposed to CIHH after 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, ferritinophagy, ferroptosis and iron metabolism related protein expression were measured, and the ferritinophagy flux in liver was further analyzed. Results Compared with CON rats, MS rats had increased liver index, damaged liver tissue morphology and function, increased total iron and free iron content, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly increased expression of ferroptosis-related proteins, reduced expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. Conclusions CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload, and alleviating ferroptosis in MS rats.

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