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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic
Xiaohong Wang1, Tao Chen1, Sizhe Chen1
1State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Abstract:
Despite advancements in interventional coronary reperfusion technologies following myocardial infarction, a notable portion of patients continue to experience elevated mortality rates as a result of myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury is crucial for devising strategies to minimize myocardial damage and enhance 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 specific deletion of cgas or Sting in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis and I/R injury. Conversely, activation of STING exacerbates ferroptosis and I/R injury. Mechanistically, STING directly targets glutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes and lysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking the STING-GPX4 interaction through mutations in T267 of STING or N146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4 administration 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 induced by anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseases associated with I/R.
Insights
Myocardial ischemia-reperfusion (MI/R) injury involves ferroptosis, a cell death pathway. The study identifies the STING-GPX4 axis, regulated by autophagy, as a key driver of ferroptosis, offering new therapeutic targets for heart disease.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Death Mechanisms
Background:
- Myocardial ischemia-reperfusion (MI/R) injury remains a significant cause of mortality despite advancements in reperfusion therapies.
- Understanding the molecular mechanisms of MI/R injury is critical for developing effective treatments to reduce cardiac damage and improve patient outcomes.
Purpose of the Study:
- To elucidate the novel mechanisms underlying MI/R injury, focusing on the role of ferroptosis and its regulators.
- To identify potential therapeutic targets for mitigating MI/R-induced myocardial damage.
Main Methods:
- Investigated the double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in cardiomyocytes during MI/R.
- Utilized genetic deletion of cGAS and STING in cardiomyocytes, assessed ferroptosis markers, and analyzed oxidative stress levels.
- Examined the interaction between STING and glutathione peroxidase 4 (GPX4) using molecular assays and in vivo models.
- Therapeutic interventions included adeno-associated virus (AAV)-mediated GPX4 administration and STING inhibition with H-151.
Main Results:
- MI/R injury is associated with the accumulation of dsDNA-cGAS-STING signaling and increased myocardial ferroptosis.
- Deletion of cGAS or STING in cardiomyocytes inhibited oxidative stress, mitigated ferroptosis, and reduced I/R injury.
- STING directly promotes GPX4 degradation via autophagy, creating a positive feedback loop that drives ferroptosis.
- Blocking the STING-GPX4 interaction or inhibiting STING stabilized GPX4, alleviated ferroptosis, and improved cardiac function post-MI/R.
Conclusions:
- A novel autophagy-dependent ferroptosis mechanism is identified in MI/R injury, mediated by the STING-GPX4 axis.
- STING-induced autophagy leads to GPX4 degradation during ischemia-reperfusion, contributing to cardiomyocyte death.
- Targeting the STING-GPX4 interaction or STING itself represents a promising therapeutic strategy for heart diseases involving I/R injury.
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