Sting Aggravates Ferroptosisdependent Myocardial Ischemiareperfusion Injury By Targeting Gpx4 For Autophagic Degradation Xiaohong Wang 1 by Xiaohong Wang 1, Tao Chen1, Sizhe Chen1, Jie Zhang 1, Liangyu Cai1, Changhao Lilei Cao1, Qian Li1, Chenghu Guo1, Qiming Deng1, Wenqian Qi1, Yonghao Hou1, Ruiun Zhang 1, Meng Zhang1✉ And Cheng Zhang 1✉ 101038/S41392025022169 instant download after payment.

Despite advancements in interventional coronary reperfusion technologies following myocardial infarction, a notable portion ofpatients continue to experience elevated mortality rates as a result of myocardial ischemia-reperfusion (MI/R) injury. An in-depthunderstanding of the mechanisms underlying MI/R injury is crucial for devising strategies to minimize myocardial damage andenhance patient survival. Here, it is discovered that during MI/R, double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal accumulates, accompanied by high rates of myocardial ferroptosis. The specificdeletion of cgas or Sting in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis1234567890();,:and I/R injury. Conversely, activation of STING exacerbates ferroptosis and I/R injury. Mechanistically, STING directly targetsglutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes andlysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking theSTING-GPX4 interaction through mutations in T267 of STING or N146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4administration alleviates ferroptosis induced by STING, resulting in enhanced cardiac functional recovery from MI/R injury.Additionally, the inhibition of STING by H-151 stabilizes GPX4 to reverse GPX4-induced ferroptosis and alleviate MI/R injury.Collectively, a novel autophagy-dependent ferroptosis mechanism is identified in this study. Specifically, STING autophagy inducedby anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseasesassociated with I/R.