Abstract

Ethyl maltol is a ubiquitous synthetic flavor enhancer. Despite its widespread use in foods, beverages, and electronic cigarettes, and its potential for environmental dispersion, its long-term cardiovascular safety remains unevaluated. Here, we employed an integrative strategy commencing with network toxicology and machine learning to identify pivotal molecular targets. The interaction between ethyl maltol and the key target was scrutinized via molecular docking and dynamics simulations. Cardiovascular toxicity was subsequently validated through in vivo and in vitro experiments, incorporating transcriptomic and single-cell RNA sequencing analyses. HMOX1 was identified as the central target. Molecular simulations confirmed stable binding between ethyl maltol and HMOX1. In mice, ethyl maltol exposure (5, 10, 20 mg/kg) induced anemia, platelet activation, reduced hindlimb perfusion, and impaired endothelium-dependent vasodilation, concomitant with upregulated vascular adhesion molecules. In human endothelial cells, ethyl maltol (10, 20, 40 μM) suppressed cell viability and triggered HMOX1 expression, NLRP3 inflammasome activation, and NF-κB signaling. Mechanistically, ethyl maltol appears to subvert the typically protective HMOX1 response into a driver of chronic vascular inflammation and adhesion. This study unveils a previously unrecognized cardiovascular risk associated with ethyl maltol, mediated through HMOX1-driven inflammatory dysregulation. It establishes a translatable paradigm for the safety assessment of prevalent food additives and environmental contaminants.