Myocardial senescence as a mechanistic endpoint of arsenic cardiotoxicity: Cysteine-associated p53/p21 activation and reversal by quercetin.

This study investigates how environmental arsenic exposure induces cardiotoxicity via myocardial senescence by in vivo/in vitro models and evaluates the protective effects of quercetin. In vivo, 3-week-old male C57BL/6 mice were exposed to sodium arsenite (NaAsO2) in drinking water at 10 or 20 mg/L for 6 weeks, with 22-month-old mice serving as a natural aging reference. In vitro, H9C2 rat cardiomyoblasts were treated with 6 μM NaAsO2 for 24 h to establish a sub-lethal senescence model, followed by PBS or 60 μM quercetin for a further 24 h. Arsenic-exposed mice exhibited dose-dependent aging-like behavioral impairment, left ventricular systolic and diastolic dysfunction, and myocardial fibrosis, driven by P53/P21 upregulation. Network toxicology and in vitro assays revealed that arsenic directly binds a p53 cysteine residue, initiating senescence through the p53/p21 axis and altering pathways including PI3K-Akt and HIF-1. At 6 μM, NaAsO2 increased the proportion of SA-β-gal-positive H9C2 cells and upregulated P53, P21, and IL-6 at both mRNA and protein levels. Network pharmacology identified TP53, AKT1, and EGFR as quercetin's core targets, with molecular docking and 100 ns dynamics simulations confirming stable, spontaneous binding. Co-treatment with 60 μM quercetin for 24 h reversed arsenic-induced senescence and downregulated these overactivated targets. Ultimately, this study provides evidence that arsenic drives myocardial senescence and associated with upregulation of the p53/p21 axis, highlighting quercetin as a promising multi-target botanical countermeasure for cardiovascular protection in arsenic-exposed populations.