Celastrol attenuates ferroptosis-mediated intestinal ischemia/reperfusion-induced acute lung injury via Hippo-YAP signaling

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-17 DOI:10.1016/j.phymed.2025.156865

Xin Fan , Yinxin Ai , Guo Mu , Feixiang Wang , Jianguo Feng , Jing Jia , Ye Chen , Jun Zhou

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引用次数: 0

Abstract

Background

Acute lung injury commonly arises as a secondary complication following intestinal ischemia/reperfusion (II/R) injury. Celastrol (CEL), recognized for its therapeutic effects on inflammation-related conditions such as acute lung injury. Its protective efficacy against II/R-induced acute lung injury remains insufficiently investigated. The Hippo-YAP signaling pathway regulates ferroptosis and plays a pivotal role in II/R injury.

Purpose

To evaluate whether CEL can activate the Hippo-YAP signaling pathway, suppress ferroptosis, and mitigate II/R-induced acute lung injury.

Methods

Firstly, an II/R model in mice was established, Immunofluorescence staining and Western blot were used to evaluate the effects of CEL on the Hippo signaling pathway and ferroptosis regulation. Network pharmacology predicted the relevance of the Hippo-YAP signaling pathway in CEL’s improvement of acute lung injury. Molecular docking experiment indicated that CEL binds effectively to yes-associated protein (YAP), and overexpression of YAP significantly alleviated both lung injury and ferroptosis. Furthermore, the oxygen-glucose deprivation/recovery (OGD/R) model of MLE-12 cells was developed to further confirm CEL’s inhibition of ferroptosis via the Hippo-YAP signaling pathway.

Results

CEL ameliorated II/R-induced acute lung injury and inhibited inflammation. In vivo and in vitro studies further revealed that CEL significantly reduced ferroptosis and reactive oxygen species (ROS) accumulation in the lung epithelial cells.

Conclusion

CEL effectively mitigated ferroptosis and II/R-induced acute lung injury through elevating YAP protein level, reducing lipid peroxidation, and decreasing intracellular iron accumulation. This study highlights CEL’s therapeutic potential for inhibiting ferroptosis, provides mechanistic insights to support CEL's broader therapeutic utility.

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Celastrol通过Hippo-YAP信号通路减轻铁中毒介导的肠缺血/再灌注诱导的急性肺损伤

背景：急性肺损伤通常是肠缺血/再灌注（II/R）损伤后的继发性并发症。Celastrol (CEL)，因其治疗炎症相关疾病（如急性肺损伤）的作用而被认可。其对II/ r诱导的急性肺损伤的保护作用尚不充分。Hippo-YAP信号通路调节铁下垂，在II/R损伤中起关键作用。目的探讨CEL是否能激活Hippo-YAP信号通路，抑制铁下垂，减轻II/ r诱导的急性肺损伤。方法首先建立小鼠II/R模型，采用免疫荧光染色和Western blot方法评价CEL对Hippo信号通路和铁凋亡的调控作用。网络药理学预测了Hippo-YAP信号通路与CEL改善急性肺损伤的相关性。分子对接实验表明，CEL与yes-associated protein （YAP）有效结合，过表达YAP可显著减轻肺损伤和铁下垂。此外，我们建立了MLE-12细胞的氧-葡萄糖剥夺/恢复（OGD/R）模型，进一步证实CEL通过希波- yap信号通路抑制铁下垂。结果scel可改善II/ r诱导的急性肺损伤，抑制炎症反应。体内和体外研究进一步表明，CEL显著降低了肺上皮细胞的铁下垂和活性氧（ROS）的积累。结论cel可通过提高YAP蛋白水平、减少脂质过氧化、降低细胞内铁积累，有效减轻铁中毒和II/ r诱导的急性肺损伤。这项研究强调了CEL抑制铁下垂的治疗潜力，为CEL更广泛的治疗用途提供了机制见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.