<i>Ex Vivo</i> Biosensor Strategy Reveals the Vascular Toxic Effects of Volatile Organic Compounds Derived from Indoor Renovation

Volatile organic compounds (VOCs) are widespread indoor gaseous pollutants that are associated with vascular diseases. However, due to methodological limitations, the underlying mechanisms of VOC-induced aortic fibrosis remains unclear. To address this gap, we established a real-world indoor renovation VOC inhalation mouse model and used an innovative <i>ex vivo</i> biosensor assay with endothelial cells to respond to serum derived from VOC exposed mice, exploring the adverse health outcomes of total VOCs on the aorta and its potential mechanisms. The <i>ex vivo</i> biosensor assay confirmed that VOCs triggered phenotypic transformation of aortic smooth muscle cells via epigenetic changes in aortic endothelial cells. Mechanistically, VOCs elevated mitochondrial DNA (mtDNA) methylation by upregulating DNMT1, leading to mtDNA leakage and subsequent activation of the cGAS-STING inflammatory pathway. By integrating real-world indoor VOC exposure with mechanistic cellular analysis, this <i>ex vivo</i> biosensor assay offers a physiologically relevant model to elucidate the systemic vascular toxicity of complex environmental mixtures. Overall, this study revealed the molecular mechanism of indoor VOC-induced aortic fibrosis based on increased mtDNA methylation in aortic endothelial cells, which mediated the phenotypic transformation of aortic smooth muscle cells. mtDNA methylation may serve as a potential target for preventing aortic fibrosis or alleviating symptoms in affected patients. Our study highlights the urgent need for improved VOC monitoring in indoor environments and provides strategies for more precise environmental risk assessments.