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

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.