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Updated: Mar 13, 2026
Herbal Munziq Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting Inflammation
Published on: January 10, 2025
ALKBH3 suppresses ischemia/reperfusion-induced PANoptosis by regulating the ZBED6/STAT1/AIM2 axis through m1A
Hongtao Diao1, Chunlei Wang2, Yuting Xiong2
1Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Background:
Myocardial ischemia/reperfusion (I/R) injury induces an intense inflammatory response and involves multiple cell death pathways. PANoptosis, an integrated cell death process involving pyroptosis, apoptosis and necroptosis, is a major driver of cardiomyocyte loss during I/R injury. However, the epitranscriptomic control of PANoptosis is poorly understood.
Methods:
We investigated the role of ALKBH3, an mRNA N1-methyladenosine (m1A) demethylase, in the regulation of cardiomyocyte PANoptosis using hypoxia/reoxygenation models in vitro and murine I/R models in vivo. Integrated transcriptomic and m1A epitranscriptomic profiling identified downstream targets. Loss- and gain-of-function studies of ALKBH3, AIM2, ZBED6 and STAT1 (siRNA or plasmid overexpression) were coupled with assessments of cell death phenotypes, inflammasome activity and gene expression. Molecular interactions and transcriptional/translational regulation were examined using co-immunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
Results:
Cardiomyocyte-restricted ALKBH3 overexpression mitigates I/R injury in vivo. Mechanistically, ALKBH3 acts as a key suppressor of PANoptosis by inhibiting AIM2. ALKBH3 demethylates m1A onZBED6 mRNA, enhancing ZBED6 translation and limiting cardiomyocyte PANoptosis. Although ZBED6 does not bind directly to the AIM2 promoter, it physically interacts with STAT1, a transcriptional activator of AIM2, and represses STAT1-driven AIM2 expression. ZBED6 overexpression reduces AIM2 levels and PANoptosis, whereas AIM2 knockout attenuates the exacerbation of cardiac injury and PANoptosis induced by ALKBH3 silencing.
Conclusions:
These findings identify the ALKBH3/ZBED6/STAT1/AIM2 signalling axis that epitranscriptomically breaks cardiomyocyte PANoptosis, highlighting a tractable therapeutic target that limits cell death and improves myocardial outcomes after I/R.
Insights
The study reveals that ALKBH3 suppresses PANoptosis, a cell death pathway in heart injury, by regulating the ZBED6/STAT1/AIM2 axis. This discovery offers a new therapeutic target for myocardial ischemia/reperfusion injury.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Epitranscriptomics
Background:
- Myocardial ischemia/reperfusion (I/R) injury triggers inflammation and cell death, notably PANoptosis, leading to cardiomyocyte loss.
- The precise epitranscriptomic regulation of PANoptosis in cardiomyocytes remains largely unelucidated.
Purpose of the Study:
- To investigate the role of ALKBH3, an N1-methyladenosine (m1A) demethylase, in regulating cardiomyocyte PANoptosis during I/R injury.
- To identify the molecular mechanisms and signaling pathways controlled by ALKBH3 in the context of cardiac I/R injury.
Main Methods:
- Utilized in vitro hypoxia/reoxygenation and in vivo murine I/R models to study ALKBH3 function.
- Employed integrated transcriptomic and m1A epitranscriptomic profiling, alongside loss- and gain-of-function studies (siRNA, plasmid overexpression) of key genes (ALKBH3, AIM2, ZBED6, STAT1).
- Assessed cell death, inflammasome activity, gene expression, and molecular interactions using co-immunoprecipitation, ChIP, and dual-luciferase reporter assays.
Main Results:
- Cardiomyocyte-specific ALKBH3 overexpression significantly reduced I/R injury in vivo.
- ALKBH3 inhibits PANoptosis by targeting the AIM2 inflammasome, specifically by demethylating m1A on ZBED6 mRNA to enhance its translation.
- ZBED6 interacts with STAT1, repressing STAT1-mediated transcription of AIM2, thereby limiting cardiomyocyte PANoptosis.
Conclusions:
- Identified a novel ALKBH3/ZBED6/STAT1/AIM2 signaling axis that epigenetically regulates cardiomyocyte PANoptosis.
- This pathway represents a promising therapeutic target for mitigating cell death and improving outcomes following myocardial I/R injury.
