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

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

doi:10.1016/j.phymed.2025.156865

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

Phytomedicine. 2025 Jul 25:143:156865. doi: 10.1016/j.phymed.2025.156865. Epub 2025 May 17.

Authors

Xin Fan¹, Yinxin Ai¹, Guo Mu¹, Feixiang Wang¹, Jianguo Feng¹, Jing Jia¹, Ye Chen², Jun Zhou³

Affiliations

¹ Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, 646000, China.
² Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, 646000, China; Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China. Electronic address: chenye0117@swmu.edu.cn.
³ Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, 646000, China. Electronic address: junzhou@swmu.edu.cn.

PMID: 40414049
DOI: 10.1016/j.phymed.2025.156865

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.

Keywords: Acute lung injury; Celastrol; Ferroptosis; Inflammation; Intestinal ischemia/reperfusion injury; YAP.

MeSH terms

Acute Lung Injury* / drug therapy
Acute Lung Injury* / etiology
Acute Lung Injury* / metabolism
Adaptor Proteins, Signal Transducing* / metabolism
Animals
Cell Cycle Proteins
Cell Line
Ferroptosis* / drug effects
Hippo Signaling Pathway
Intestines* / blood supply
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Pentacyclic Triterpenes* / pharmacology
Protein Serine-Threonine Kinases / metabolism
Reperfusion Injury* / complications
Reperfusion Injury* / drug therapy
Signal Transduction / drug effects
Transcription Factors / metabolism
Triterpenes* / pharmacology
YAP-Signaling Proteins

Substances

Pentacyclic Triterpenes
YAP-Signaling Proteins
celastrol
Yap1 protein, mouse
Protein Serine-Threonine Kinases
Triterpenes
Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Transcription Factors