Postconditioning with Irisin Attenuates Lung Ischemia/Reperfusion Injury by Suppressing Ferroptosis via Induction of the Nrf2/HO‐1 Signal Axis
Yun Wang, Zhe Dong, Zongze Zhang, Yanlin Wang, Kun Yang, Xinyi Li
Abstract
Iron‐dependent lipid peroxidation causes ferroptosis. This study was aimed at verifying that irisin postconditioning can inhibit ferroptosis and minimize lung ischemia/reperfusion (I/R) damage via activating the Nrf2/HO‐1 signal axis. We constructed a murine model of I/R lung damage. At the onset of reperfusion, irisin, ferroptosis inhibitor ferrostatin‐1, and ferroptosis inducer Fe‐citrate were all administered. We discovered that irisin could reduce lung I/R injury, consistent with ferrostatin‐1’s action. Furthermore, irisin suppressed ferroptosis in lung I/R damage, as evidenced by lower ROS, MDA, and Fe 2+ , as well as alterations in critical protein expression (GPX4 and ACSL4). However, Fe‐citrate abolished the protective effects of irisin. Transcriptome research found that irisin increased the mRNA levels of Nrf2 and HO‐1. Thus, we used siRNA to investigate the role of the Nrf2/HO‐1 axis in irisin‐mediated protection against hypoxia/reoxygenation (H/R) damage in MLE‐12 cells. Irisin consistently reduced ferroptosis and improved mitochondrial dysfunction caused by H/R. Irisin’s cytoprotective function was eliminated when Nrf2 was silenced. As a result, irisin postconditioning may protect against lung I/R damage by suppressing ferroptosis via the Nrf2/HO‐1 signaling axis.