Hydrogen alleviates cardiac ferroptosis damage under chronic intermittent hypoxia conditions by targeting Nrf2

Objective: Obstructive sleep apnea (OSA) is a common disorder for which comprehensive and effective treatments and interventions have not yet been fully developed. A hallmark of OSA is chronic intermittent hypoxia (CIH), which significantly contributes to the pathogenesis of cardiovascular diseases through mechanisms such as Ferroptosis. Hydrogen is known for its selective antioxidant properties, however its inhibitory effects on CIH-induced Ferroptosis and the associated molecular mechanisms remain insufficiently characterized. This study aims to elucidate the effects of hydrogen on CIH-induced Ferroptosis and to explore the potential molecular pathways involved.

Methods: In vivo and in vitro CIH models were established to observe changes in cardiac function and pathological damage. Use transcriptomics analysis to identify potential targets. Additionally, probes, electron microscopy, and related assay kits were employed to assess oxidative stress and Ferroptosis.

Results: Hydrogen could mitigate cardiac injury and Ferroptosis induced by CIH, primarily through its sustained modulation of oxidative stress and the activation of Autophagy. Hydrogen has been observed to reduce Ferroptosis in H9C2 cells induced by RSL3, with effects comparable to those of Mito Q, Fer-1, and the Nrf2 activator SA. Importantly, the protective effects of hydrogen against Ferroptosis were negated by the application of the Autophagy inhibitor 3-MA, the Nrf2 inhibitor ML385 and si-Nfe2l2 gene.

Conclusion: These findings suggested that hydrogen could promote Autophagy and reduce oxidative stress by activating the Nrf2 protein, thereby inhibiting Ferroptosis and alleviating cardiac damage caused by CIH.

Autophagy; Chronic intermittent hypoxia; Ferroptosis; Hydrogen; Nrf2; Oxidative stress.