Mitochondrial DNA‐cGAS‐STING induces macrophage pyroptosis via phospho‐IRF3‐mediated NLRP3 expression in ionising radiation‐induced atherosclerosis progression

BACKGROUND AND PURPOSE: Ionising radiation (IR) is a major cancer-treatment modality, yet the mechanisms driving IR-triggered cardiovascular injury are poorly defined. This work aimed to uncover how IR accelerates atherosclerosis (AS) and the underlying molecular mechanisms. EXPERIMENTAL APPROACH: We applied 9.4 T magnetic resonance imaging to evaluate atherosclerotic lesions. Single-cell RNA sequencing was performed on carotid arteries. Apolipoprotein E (ApoE) knockout mice with caspase-1 deletion and macrophage-specific cGAS knockdown were used for in vivo validation. JASPAR prediction and dual-luciferase reporter assays were implemented to verify transcriptional regulation of NLRP3. KEY RESULTS: IR substantially aggravated atherosclerotic progression, accompanied by elevated pyroptosis-related gene expression in macrophages within atherosclerotic plaques. Mechanistically, IR promoted cytoplasmic mtDNA release to activate the cGAS/STING/TBK1 axis and cause p-IRF3 nuclear translocation. Phosphorylated IRF3 bound to the NLRP3 promoter and enhanced its transcription. Genetic ablation of caspase-1 or macrophage-specific cGAS knockdown alleviated IR-driven AS progression. CONCLUSIONS AND IMPLICATIONS: Macrophage pyroptosis drives IR-accelerated AS progression through the mtDNA/cGAS/STING/p-IRF3 axis-dependent transcriptional up-regulation of NLRP3. Targeting the cGAS-STING pathway may provide a therapeutic strategy for IR-associated atherosclerotic plaque progression.