Investigation of the anti-hypertrophic and toxicological effects of quinoxaline derivative N8 mediated by H3K27me3 upregulation.

Myocardial hypertrophy is a pathological remodeling process characterized by cardiomyocyte enlargement and cardiac dysfunction. Its high prevalence and strong association with heart failure and arrhythmias constitute a major public health burden. Currently, pharmacological options that effectively halt or reverse this condition remain limited. The Jumonji domain-containing protein 3 (JMJD3)-specific inhibitor GSK-J4 has emerged as a potential anti-hypertrophic agent, we used GSK-J4 as a lead compound to design and synthesize a novel derivative. Compound N8, which exhibits potent anti-hypertrophic activity coupled with lower cytotoxicity compared to GSK-J4 and prazosin. In addition, compound N8 serves as a multiorgan protective agent that not only rescues pressure-overload- induced cardiac dysfunction but also prevents consequent injury to the liver and kidneys. Collectively, our data support the further development of novel targeted therapies for pathological cardiac hypertrophy.