Atraric acid attenuates chronic intermittent hypoxia-induced lung injury by inhibiting ferroptosis through activation of the NRF2 pathway

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-08-31 DOI:10.1016/j.taap.2025.117540

Jingjing Chen , Lu Zhou , Mengxin Li , Jun Wang , Yaru Chen , Jing Xia , Yue Lin , Huizhen Chen , Zibo Dong

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Abstract

Chronic Intermittent Hypoxia (CIH) is a central pathological feature of diseases such as obstructive sleep apnea hypopnea syndrome (OSAHS), which induces oxidative stress in lung tissues and leads to lung injury. Atraric acid (AA), a lichen-derived compound, has been reported to possess anti-inflammatory and antioxidant activities. In this study, we investigated the functions and mechanisms of AA in CIH-induced lung injury by constructing a CIH mouse model and an in vitro hypoxia/reoxygenation model in MLE-12 cells. Various methods were employed, including hematoxylin and eosin (H&E) staining, biochemical assay kits, quantitative polymerase chain reaction (qPCR) analysis, protein blotting, immunofluorescence, and flow cytometry. The results showed that AA pretreatment significantly attenuated pathological injury of mouse lung tissue, reduced pulmonary edema, reactive oxygen species (ROS) and malondialdehyde production, as well as the depletion of total antioxidant capacity, catalase and glutathione, and lowered the expression levels of inflammatory factors. Mechanistic studies showed that AA up-regulated solute transport family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression and down-regulated prostaglandin-endoperoxide synthase 2 (PTGS2) through activation of the Nrf2 signaling pathway, whereas the Nrf2 inhibitor ML385 completely blocked this protective effect. In conclusion, the present study demonstrates that AA targets the Nrf2 axis, attenuated CIH-induced inflammation, alleviates ROS accumulation, and blocks the vicious cycle of oxidative stress, ferroptosis, and inflammation, making it a promising therapeutic strategy for the treatment of CIH-induced lung injury.

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白曲酸通过激活NRF2通路抑制铁下垂，减轻慢性间歇性缺氧引起的肺损伤

慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停低通气综合征（OSAHS）等疾病的中心病理特征，可诱导肺组织氧化应激，导致肺损伤。白屈酸（AA）是一种地衣衍生化合物，据报道具有抗炎和抗氧化活性。本研究通过构建CIH小鼠模型和MLE-12细胞体外缺氧/再氧化模型，探讨AA在CIH诱导肺损伤中的作用及机制。采用多种方法，包括苏木精和伊红（H&；E）染色、生化试剂盒、定量聚合酶链反应（qPCR）分析、蛋白质印迹、免疫荧光和流式细胞术。结果表明，AA预处理可显著减轻小鼠肺组织病理损伤，减少肺水肿、活性氧（ROS）和丙二醛的产生，降低总抗氧化能力、过氧化氢酶和谷胱甘肽的消耗，降低炎症因子的表达水平。机制研究表明，AA通过激活Nrf2信号通路上调溶质转运家族7成员11 （SLC7A11）和谷胱甘肽过氧化物酶4 （GPX4）的表达，下调前列腺素内过氧化物合成酶2 （PTGS2）的表达，而Nrf2抑制剂ML385完全阻断了这一保护作用。综上所述，本研究表明，AA靶向Nrf2轴，减轻cih诱导的炎症，减轻ROS积累，阻断氧化应激、铁下沉、炎症的恶性循环，是治疗cih诱导的肺损伤的一种有前景的治疗策略。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.