2-Methoxyestradiol attenuates lung injury induced by chronic intermittent hypoxia via inhibiting the HIF1-α/SLC7A11 pathway.

Ferroptosis is a novel type of programmed cell death associated with lung injury induced by chronic intermittent hypoxia (CIH). 2-Methoxyestradiol (2-ME2), as an inhibitor of Hypoxia-inducible factor 1 alpha (HIF-1α), affects HIF-1α-related biological processes. This study aimed to explore the role and mechanism of 2-ME2 on CIH-induced lung injury. CIH-associated lung injury was verified in SD rats. 2-ME2 was administered intraperitoneally at a dosage of 20 mg/kg to verify its treatment efficacy. CIH treated Human bronchoalveolar epithelial cells (BEAS-2B) were used to explore the mechanism of 2-ME2. HIF-1α knockdown cell lines and SLC7A11-overexpressing cell lines were established to explore the role of HIF-1α/SLC7A11 pathway in CIH-induced ferroptosis. The ChIP-qPCR was employed to determine the presence of binding sites between HIF-1α and the SLC7A11 promoter region. In vivo experiments demonstrated that, in comparison with the control group, there was an increase in lung injury scores and collagen ratio in the lung tissue of rats belonging to the CIH group, along with an upregulation of HIF-1α expression and alterations in the expression of ferroptosis-related genes (all p < 0.05). 2-ME2 mitigated the lung injury and ferroptosis induced by CIH in vivo. In vitro experiments revealed that, compared to BEAS-2B cells under normoxic conditions, HIF-1α expression increased significantly in BEAS-2B cells exposed to CIH. This was accompanied by alterations in the expression of ferroptosis-related genes (all p < 0.05) and an increase in both reactive oxygen species (ROS) and Fe(2+) levels (both p < 0.05). HIF-1α knockdown, or SLC7A11 overexpression, reversed CIH-induced BEAS-2B cell ferroptosis. ChIP-qPCR confirmed the direct interaction between HIF-1α and SLC7A11 promoter region. The HIF-1α inhibitor, 2-ME2, effectively reverses CIH-induced lung tissue ferroptosis. The potential mechanism of 2-ME2 in inhibiting ferroptosis may involve suppressing the HIF-1α/SLC7A11 pathway.